NM_000350.3:c.455G>A

Variant names:

• chr1-94103130-C-T
• rs62646862
• NM_000350.3:c.455G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1 PP2 BP4_Strong BP6 BS2

The NM_000350.3(ABCA4):​c.455G>A​(p.Arg152Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,613,942 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts 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. R152R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (25 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:7 O:2
• Conservation: PhyloP100: 1.22
• Publications: 23 publications found

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]

ABCA4 Gene-Disease associations (from GenCC):

• ABCA4-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cone-rod dystrophy 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• retinitis pigmentosa 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Stargardt disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000350.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 578 curated pathogenic missense variants (we use a threshold of 10). The gene has 28 curated benign missense variants. Gene score misZ: -0.65813 (below the threshold of 3.09). Trascript score misZ: 1.3628 (below the threshold of 3.09). GenCC associations: The gene is linked to cone-rod dystrophy 3, retinitis pigmentosa 19, ABCA4-related retinopathy, severe early-childhood-onset retinal dystrophy, cone-rod dystrophy, Stargardt disease, retinitis pigmentosa.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010893583).
• BP6: Variant 1-94103130-C-T is Benign according to our data. Variant chr1-94103130-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99301.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.455G>A	p.Arg152Gln	missense_variant	Exon 5 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.455G>A	p.Arg152Gln	missense_variant	Exon 5 of 49		NP_001412253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.455G>A	p.Arg152Gln	missense_variant	Exon 5 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.455G>A	p.Arg152Gln	missense_variant	Exon 5 of 19			ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152150 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00259 AC: 651 AN: 251232 AF XY: 0.00258

Gnomad AFR exome AF: 0.000863

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00370

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00442 AC: 6461 AN: 1461674 Hom.: 25 Cov.: 32 AF XY: 0.00434 AC XY: 3156 AN XY: 727160

African (AFR) AF: 0.000568 AC: 19 AN: 33472

American (AMR) AF: 0.00273 AC: 122 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00302 AC: 260 AN: 86226

European-Finnish (FIN) AF: 0.000787 AC: 42 AN: 53384

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00516 AC: 5735 AN: 1111898

Other (OTH) AF: 0.00459 AC: 277 AN: 60378

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152268 Hom.: 3 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74452

African (AFR) AF: 0.000867 AC: 36 AN: 41540

American (AMR) AF: 0.00477 AC: 73 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4832

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00431 AC: 293 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00359 Hom.: 1

Bravo AF: 0.00298

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00239 AC: 290

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:7 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5 Other:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCA4 p.Arg152Gln variant was identified in 5 of 958 proband chromosomes (frequency: 0.005) from individuals or families with Stargardt Disease and Age-related Macular Degeneration and was present in 3 of 440 control chromosomes (frequency: 0.0068) from healthy individuals (Rivera_2000_PMID:10958763; Schulz_2017_PMID:28118664). The variant was also identified in dbSNP (ID: rs62646862), LOVD 3.0 and in ClinVar (classified as likely benign by EGL Genetics, GeneDx and ARUP Laboratories and as likely pathogenic by the University Regensberg Institute of Human Genetics). The variant was not identified in Cosmic. The variant was identified in control databases in 651 of 251232 chromosomes (2 homozygous) at a frequency of 0.002591 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: European (non-Finnish) in 420 of 113574 chromosomes (freq: 0.003698), South Asian in 96 of 30610 chromosomes (freq: 0.003136), Other in 18 of 6136 chromosomes (freq: 0.002934), Latino in 86 of 34578 chromosomes (freq: 0.002487), African in 14 of 16230 chromosomes (freq: 0.000863) and European (Finnish) in 17 of 21646 chromosomes (freq: 0.000785); it was not observed in the Ashkenazi Jewish and East Asian populations. The p.Arg152 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA4: BP4, BS2 -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 27, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11702214, 23143460, 22264887, 11385708, 26593885, 14517951, 15192030, 25444351, 28118664, 22328824, 15161829, 10958763, 23953153, 16917483, 26764160, 28898540, 29925512, 30093795, 31456290) -

Oct 20, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt disease Pathogenic:1 Other:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 06-25-2018 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

ABCA4-related disorder Uncertain:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Aug 28, 2024

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). -

Severe early-childhood-onset retinal dystrophy Uncertain:1

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The ABCA4 c.455G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: BS1, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

Retinal dystrophy Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 21, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		1.2
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.43
Sift	Benign	0.12	T;.
Sift4G	Benign	0.22	T;.
Polyphen		0.012	B;.
Vest4		0.16
MVP		0.88
MPC		0.098
ClinPred		0.031	T
GERP RS		2.6
Varity_R		0.058
gMVP		0.66
Mutation Taster		=79/21	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs62646862; hg19: chr1-94568686; COSMIC: COSV104677865;