rs4147831

Positions:

• chr1-94078677-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

LOC124904222 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 99041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94078677-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.1269C>T	p.His423His	synonymous_variant	10/50	ENST00000370225.4	NP_000341.2
ABCA4	NM_001425324.1	c.1269C>T	p.His423His	synonymous_variant	10/49		NP_001412253.1
LOC124904222	XR_007066231.1	n.203-5052G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.1269C>T	p.His423His	synonymous_variant	10/50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.1269C>T	p.His423His	synonymous_variant	10/19			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

GnomAD3 exomes AF: 0.0873 AC: 21948 AN: 251476 Hom.: 1071 AF XY: 0.0842 AC XY: 11449 AN XY: 135914

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 SAS exome AF: 0.0927

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

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.0294

Gnomad4 EAS exome AF: 0.134

Gnomad4 SAS exome AF: 0.0883

Gnomad4 FIN exome AF: 0.0578

Gnomad4 NFE exome AF: 0.0776

Gnomad4 OTH exome AF: 0.0819

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

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0240

Gnomad4 EAS AF: 0.133

Gnomad4 SAS AF: 0.0896

Gnomad4 FIN AF: 0.0532

Gnomad4 NFE AF: 0.0749

Gnomad4 OTH AF: 0.0802

Alfa AF: 0.0766 Hom.: 1133

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2011	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 07, 2014	- -

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Stargardt Disease, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

ABCA4-related disorder Benign:1

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. -

Cone-Rod Dystrophy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Macular degeneration Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.11
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs4147831; hg19: chr1-94544233; COSMIC: COSV64672022;