chr1-94001891-G-A

Position:

chr1-94001891-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000350.3(ABCA4):c.6249C>T(p.Ile2083=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0725 in 1,614,070 control chromosomes in the GnomAD database, including 6,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I2083I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.13 ( 2077 hom., cov: 33)

Exomes 𝑓: 0.067 ( 4449 hom. )

Consequence

ABCA4
NM_000350.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -1.43

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]

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 1-94001891-G-A is Benign according to our data. Variant chr1-94001891-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 99440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94001891-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.43 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.6249C>T	p.Ile2083=	synonymous_variant	45/50	ENST00000370225.4
ABCA4	XM_047416704.1 linkuse as main transcript	c.6027C>T	p.Ile2009=	synonymous_variant	44/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.6249C>T	p.Ile2083=	synonymous_variant	45/50	1	NM_000350.3	P1
ABCA4	ENST00000465352.1 linkuse as main transcript	n.665C>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes

AF:

0.127

AC:

19385

AN:

152094

Hom.:

2080

Cov.:

show subpopulations

Gnomad AFR

AF:

0.293

Gnomad AMI

AF:

0.223

Gnomad AMR

AF:

0.0788

Gnomad ASJ

AF:

0.0974

Gnomad EAS

AF:

0.0583

Gnomad SAS

AF:

0.0704

Gnomad FIN

AF:

0.0334

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.0621

Gnomad OTH

AF:

0.119

GnomAD3 exomes

AF:

0.0767

AC:

19277

AN:

251396

Hom.:

1225

AF XY:

0.0727

AC XY:

9880

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.304

Gnomad AMR exome

AF:

0.0527

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.0615

Gnomad SAS exome

AF:

0.0716

Gnomad FIN exome

AF:

0.0369

Gnomad NFE exome

AF:

0.0602

Gnomad OTH exome

AF:

0.0793

GnomAD4 exome

AF:

0.0668

AC:

97599

AN:

1461858

Hom.:

4449

Cov.:

AF XY:

0.0667

AC XY:

48512

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.307

Gnomad4 AMR exome

AF:

0.0552

Gnomad4 ASJ exome

AF:

0.110

Gnomad4 EAS exome

AF:

0.0507

Gnomad4 SAS exome

AF:

0.0710

Gnomad4 FIN exome

AF:

0.0368

Gnomad4 NFE exome

AF:

0.0594

Gnomad4 OTH exome

AF:

0.0845

GnomAD4 genome

AF:

0.127

AC:

19404

AN:

152212

Hom.:

2077

Cov.:

AF XY:

0.125

AC XY:

9287

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.293

Gnomad4 AMR

AF:

0.0785

Gnomad4 ASJ

AF:

0.0974

Gnomad4 EAS

AF:

0.0581

Gnomad4 SAS

AF:

0.0690

Gnomad4 FIN

AF:

0.0334

Gnomad4 NFE

AF:

0.0621

Gnomad4 OTH

AF:

0.123

Alfa

AF:

0.0768

Hom.:

569

Bravo

AF:

0.139

Asia WGS

AF:

0.111

AC:

388

AN:

3478

EpiCase

AF:

0.0692

EpiControl

AF:

0.0674

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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)	Aug 25, 2014	- -

not provided

Benign:1Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 15, 2021

- -

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

-0.36

CADD

Benign

0.18

DANN

Benign

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over