rs4147831

Variant names:

• chr1-94078677-G-A
• rs4147831
• NM_000350.3:c.1269C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-94078677-G-A
• chr1-94078677-G-C
• chr1-94078677-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000350.3(ABCA4):​c.1269C>T​(p.His423His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0819 in 1,608,676 control chromosomes in the GnomAD database, including 5,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (773 hom., cov: 26)
  • Exomes 𝑓: 0.081 (5045 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: -0.965
• Publications: 24 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

LOC124904222 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-94078677-G-A is Benign according to our data. Variant chr1-94078677-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.965 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.1269C>T	p.His423His	synonymous_variant	Exon 10 of 50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.1269C>T	p.His423His	synonymous_variant	Exon 10 of 49		NP_001412253.1
LOC124904222	XR_007066231.1	n.203-5052G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.1269C>T	p.His423His	synonymous_variant	Exon 10 of 50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.1269C>T	p.His423His	synonymous_variant	Exon 10 of 19			ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14151 AN: 150748 Hom.: 775 Cov.: 26

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0240

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.0908

Gnomad FIN AF: 0.0532

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0749

Gnomad OTH AF: 0.0749

GnomAD2 exomes AF: 0.0873 AC: 21948 AN: 251476 AF XY: 0.0842

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.0598

Gnomad NFE exome AF: 0.0740

Gnomad OTH exome AF: 0.0780

GnomAD4 exome AF: 0.0807 AC: 117653 AN: 1457812 Hom.: 5045 Cov.: 39 AF XY: 0.0801 AC XY: 58058 AN XY: 725258

African (AFR) AF: 0.129 AC: 4294 AN: 33372

American (AMR) AF: 0.121 AC: 5407 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 765 AN: 26004

East Asian (EAS) AF: 0.134 AC: 5278 AN: 39474

South Asian (SAS) AF: 0.0883 AC: 7609 AN: 86216

European-Finnish (FIN) AF: 0.0578 AC: 3070 AN: 53124

Middle Eastern (MID) AF: 0.0415 AC: 238 AN: 5736

European-Non Finnish (NFE) AF: 0.0776 AC: 86068 AN: 1109154

Other (OTH) AF: 0.0819 AC: 4924 AN: 60138

GnomAD4 genome AF: 0.0939 AC: 14161 AN: 150864 Hom.: 773 Cov.: 26 AF XY: 0.0933 AC XY: 6867 AN XY: 73588

African (AFR) AF: 0.132 AC: 5419 AN: 41100

American (AMR) AF: 0.115 AC: 1732 AN: 15040

Ashkenazi Jewish (ASJ) AF: 0.0240 AC: 83 AN: 3464

East Asian (EAS) AF: 0.133 AC: 675 AN: 5068

South Asian (SAS) AF: 0.0896 AC: 426 AN: 4754

European-Finnish (FIN) AF: 0.0532 AC: 546 AN: 10264

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0749 AC: 5085 AN: 67864

Other (OTH) AF: 0.0802 AC: 169 AN: 2106

Alfa AF: 0.0804 Hom.: 2587

Bravo AF: 0.101

Asia WGS AF: 0.129 AC: 447 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Benign:3

Aug 12, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis Pigmentosa, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Stargardt Disease, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCA4-related disorder Benign:1

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. -

Cone-Rod Dystrophy, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Macular degeneration Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.11
DANN	Benign	0.39
PhyloP100		-0.96
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4147831; hg19: chr1-94544233; COSMIC: COSV64672022;