1-94103119-T-C

Position:

• chr1-94103119-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

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 Benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (9 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:8 O:1
• Conservation: PhyloP100: 0.761

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM1: In a disulfide_bond (size 249) in uniprot entity ABCA4_HUMAN there are 150 pathogenic changes around while only 8 benign (95%) in NM_000350.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.009164572).
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.466A>G	p.Ile156Val	missense_variant	5/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.466A>G	p.Ile156Val	missense_variant	5/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.466A>G	p.Ile156Val	missense_variant	5/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000649773.1	c.466A>G	p.Ile156Val	missense_variant	5/19			ENSP00000496882

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152220 Hom.: 2 Cov.: 33

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

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

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

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:7 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:5 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2018	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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 20, 2021	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ABCA4: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2016	- -

ABCA4-related disorder Benign:2

Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 04, 2019	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). -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2015

- -

Abnormal retinal morphology Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Severe early-childhood-onset retinal dystrophy;C1858806:Cone-rod dystrophy 3;C1866422:Retinitis pigmentosa 19;C3495438:Age related macular degeneration 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Severe early-childhood-onset retinal dystrophy Benign:1

Likely benign, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

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;.
MutationTaster	Benign	0.99	D;D
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

Other links and lift over

dbSNP: rs62646863; hg19: chr1-94568675;