rs62646863

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_StrongBS1BS2

The NM_000350.3(ABCA4):​c.466A>G​(p.Ile156Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,124 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I156I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0020 ( 9 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:8O:1

Conservation

PhyloP100: 0.761
Variant links:
Genes affected
ABCA4 (HGNC:34): (ATP binding cassette subfamily A member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This protein is a retina-specific ABC transporter with N-retinylidene-PE as a substrate. It is expressed exclusively in retina photoreceptor cells, and the gene product mediates transport of an essental molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane. Mutations in this gene are found in patients diagnosed with Stargardt disease, a form of juvenile-onset macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus, and macular degeneration age-related 2. [provided by RefSeq, Sep 2019]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000350.3
BP4
Computational evidence support a benign effect (MetaRNN=0.009164572).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00218 (332/152338) while in subpopulation AMR AF= 0.0106 (162/15298). AF 95% confidence interval is 0.00926. There are 2 homozygotes in gnomad4. There are 168 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCA4NM_000350.3 linkc.466A>G p.Ile156Val missense_variant Exon 5 of 50 ENST00000370225.4 NP_000341.2 P78363Q6AI28
ABCA4NM_001425324.1 linkc.466A>G p.Ile156Val missense_variant Exon 5 of 49 NP_001412253.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCA4ENST00000370225.4 linkc.466A>G p.Ile156Val missense_variant Exon 5 of 50 1 NM_000350.3 ENSP00000359245.3 P78363
ABCA4ENST00000649773.1 linkc.466A>G p.Ile156Val missense_variant Exon 5 of 19 ENSP00000496882.1 A0A3B3IRV8

Frequencies

GnomAD3 genomes
AF:
0.00218
AC:
332
AN:
152220
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000290
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0106
Gnomad ASJ
AF:
0.00202
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00198
Gnomad OTH
AF:
0.00717
GnomAD3 exomes
AF:
0.00147
AC:
370
AN:
251380
Hom.:
1
AF XY:
0.00149
AC XY:
203
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00321
Gnomad ASJ exome
AF:
0.00189
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.00190
Gnomad OTH exome
AF:
0.00277
GnomAD4 exome
AF:
0.00197
AC:
2883
AN:
1461786
Hom.:
9
Cov.:
32
AF XY:
0.00190
AC XY:
1384
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.00400
Gnomad4 ASJ exome
AF:
0.00145
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.000112
Gnomad4 NFE exome
AF:
0.00226
Gnomad4 OTH exome
AF:
0.00229
GnomAD4 genome
AF:
0.00218
AC:
332
AN:
152338
Hom.:
2
Cov.:
33
AF XY:
0.00226
AC XY:
168
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.000289
Gnomad4 AMR
AF:
0.0106
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.00198
Gnomad4 OTH
AF:
0.00710
Alfa
AF:
0.00195
Hom.:
0
Bravo
AF:
0.00262
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00151
AC:
13
ExAC
AF:
0.00131
AC:
159
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00185
EpiControl
AF:
0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:8Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4Benign:5Other:1
-
Retina International
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Nov 09, 2018
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The I156V variant has been reported in a patient diagnosed with Stargardt disease and was absent from 96 control alleles (Papaioannou et al., 2000). The I156V variant has also been reported as a polymorphism (Riveiro-Alvarez et al.,2009). The NHLBI Exome Sequencing Project and the 1000 Genomes Project reports that I156V was observed in 13/8600 alleles from individuals of European background, in 1/28 alleles from individuals of Spanish background and in 2/196 alleles from individuals of Italian background indicating it may be a rare benign variant in the European population. The I156V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (R152Q, I153L, E161K, G172S) have been reported in the Human Gene Mutation Database in association with ABCA4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. -

Aug 20, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The ABCA4 c.466A>G; p.Ile156Val variant (rs62646863) is reported in the literature in individuals affected with retinis pigmentosa, Stargardt disease, or another retinopathy, though it has not been demonstrated to be disease-causing (Ducroq 2002, Oldani 2012, Papaioannou 2000, Passerini 2010, Riveiro-Alvarez 2009, Valverde 2007). While this variant has been described in an affected individual with a second pathogenic variant (Ducroq 2002), it has also been described in healthy controls (Riveiro-Alvarez 2009) and in affected individuals carrying two other pathogenic variants that could explain their symptoms (Oldani 2012, Passerini 2010). The p.Ile156Val variant is found in the Latino population with an overall allele frequency of 0.33% (117/35438 alleles, including one homozygote) in the Genome Aggregation Database. The isoleucine at codon 156 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to conflicting information, the clinical significance of the p.Ile156Val variant is uncertain at this time. References: Ducroq D et al. The ABCA4 gene in autosomal recessive cone-rod dystrophies. Am J Hum Genet. 2002 Dec;71(6):1480-2. Oldani M et al. Clinical and molecular genetic study of 12 Italian families with autosomal recessive Stargardt disease. Genet Mol Res. 2012 Dec 17;11(4):4342-50. Papaioannou M et al. An analysis of ABCR mutations in British patients with recessive retinal dystrophies. Invest Ophthalmol Vis Sci. 2000 Jan;41(1):16-9. Passerini I et al. Novel mutations in of the ABCR gene in Italian patients with Stargardt disease. Eye (Lond). 2010 Jan;24(1):158-64. Riveiro-Alvarez R et al. Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease. Br J Ophthalmol. 2009 Oct;93(10):1359-64. Valverde D et al. Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients. Invest Ophthalmol Vis Sci. 2007 Mar;48(3):985-90. -

Oct 27, 2016
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ABCA4: BP4, BS2 -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The ABCA4 p.Ile156Val variant was identified in 22 of 9152 proband chromosomes (freq=0.0024) from individuals or families with ABCA4-associated diseases, including Stargardt disease, retinitis pigmentosa and retinal dystrophies; the variant was also found in 5 of 348 chromosomes (freq=0.014) from healthy controls (Fujinami_2013_PMID:23982839; Cornelis_2017_PMID:28044389; Oldani_2012_PMID:23096905; Zernant_2011_PMID:21911583; Riviero-Alvarez_2009_PMID:18977788; Ducrog_2002_PMID:12515255; Papaioannou_2000_PMID:10634594, Valverde_2007_PMID:17325136; Passerini_2010_PMID:19265867). The variant was also identified in dbSNP (ID: rs62646863), Cosmic, LOVD 3.0 and ClinVar (classified as a VUS by GeneDx in 2017, EGL Genetic Diagnostics in 2016, Ambry Genetics in 2015, Center for Mendelian Genomics at University Medical Centre Ljubjana in 2017 and classified as likely benign by NIHR Bioresource Rare Diseases, University of Cambridge in 2015). The p.Ile156Val variant was identified in control databases in 408 of 282784 chromosomes (1 homozygous) at a frequency of 0.001443 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 117 of 35438 chromosomes (freq: 0.003302), Other in 18 of 7226 chromosomes (freq: 0.002491), Ashkenazi Jewish in 21 of 10368 chromosomes (freq: 0.002025), European (non-Finnish) in 242 of 129102 chromosomes (freq: 0.001874), African in 4 of 24960 chromosomes (freq: 0.00016), European (Finnish) in 3 of 25122 chromosomes (freq: 0.000119), South Asian in 2 of 30614 chromosomes (freq: 0.000065), and East Asian in 1 of 19954 chromosomes (freq: 0.00005). The I156V variant was identified in 2/29 families with ABCA4-related conditions, one with Stargardt disease and one with cone dystrophy, although the variant was not suggested to be causal in either case (Gonz√°lez-del Pozo_2018_PMID:30190494). The variant was also identified in a proband with early-onset (diagnosed at 14) retinitis pigmentosa, however this variant was suggested to be benign (Hubshman_2018_PMID:29272404). The p.Ile156 residue is not conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. In addition, the variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

ABCA4-related disorder Benign:2
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Oct 04, 2019
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Uncertain:1
Aug 07, 2015
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Abnormal retinal morphology Uncertain:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1
Jan 01, 2012
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Severe early-childhood-onset retinal dystrophy Benign:1
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Uncertain
0.040
CADD
Benign
5.0
DANN
Benign
0.76
DEOGEN2
Benign
0.33
T;.
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.69
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.71
T;T
M_CAP
Benign
0.065
D
MetaRNN
Benign
0.0092
T;T
MetaSVM
Benign
-0.72
T
MutationAssessor
Uncertain
2.7
M;.
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.46
N;.
REVEL
Uncertain
0.51
Sift
Benign
0.70
T;.
Sift4G
Benign
0.55
T;.
Polyphen
0.0020
B;.
Vest4
0.67
MVP
0.58
MPC
0.073
ClinPred
0.020
T
GERP RS
-1.2
Varity_R
0.036
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs62646863; hg19: chr1-94568675; API