rs6666652

Positions:

chr1-93996161-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000370225.4(ABCA4):c.6764G>T(p.Ser2255Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 1,613,784 control chromosomes in the GnomAD database, including 10,691 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 4974 hom., cov: 33)

Exomes 𝑓: 0.051 ( 5717 hom. )

Consequence

ABCA4
ENST00000370225.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 0.742

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2466311E-4).

BP6

Variant 1-93996161-C-A is Benign according to our data. Variant chr1-93996161-C-A is described in ClinVar as [Benign]. Clinvar id is 99494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-93996161-C-A is described in Lovd as [Pathogenic]. Variant chr1-93996161-C-A is described in Lovd as [Likely_benign]. Variant chr1-93996161-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.6764G>T	p.Ser2255Ile	missense_variant	49/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1 linkuse as main transcript	c.6542G>T	p.Ser2181Ile	missense_variant	48/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.6764G>T	p.Ser2255Ile	missense_variant	49/50	1	NM_000350.3	ENSP00000359245	P1

Frequencies

GnomAD3 genomes

AF:

0.165

AC:

25160

AN:

152116

Hom.:

4967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.480

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.0925

Gnomad ASJ

AF:

0.0616

Gnomad EAS

AF:

0.0227

Gnomad SAS

AF:

0.0553

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.134

Gnomad NFE

AF:

0.0411

Gnomad OTH

AF:

0.146

GnomAD3 exomes

AF:

0.0715

AC:

17958

AN:

251210

Hom.:

2287

AF XY:

0.0630

AC XY:

8559

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.494

Gnomad AMR exome

AF:

0.0617

Gnomad ASJ exome

AF:

0.0682

Gnomad EAS exome

AF:

0.0270

Gnomad SAS exome

AF:

0.0499

Gnomad FIN exome

AF:

0.00578

Gnomad NFE exome

AF:

0.0400

Gnomad OTH exome

AF:

0.0660

GnomAD4 exome

AF:

0.0511

AC:

74676

AN:

1461550

Hom.:

5717

Cov.:

AF XY:

0.0499

AC XY:

36308

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.499

Gnomad4 AMR exome

AF:

0.0657

Gnomad4 ASJ exome

AF:

0.0702

Gnomad4 EAS exome

AF:

0.0230

Gnomad4 SAS exome

AF:

0.0506

Gnomad4 FIN exome

AF:

0.00682

Gnomad4 NFE exome

AF:

0.0381

Gnomad4 OTH exome

AF:

0.0734

GnomAD4 genome

AF:

0.166

AC:

25199

AN:

152234

Hom.:

4974

Cov.:

AF XY:

0.160

AC XY:

11934

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.480

Gnomad4 AMR

AF:

0.0922

Gnomad4 ASJ

AF:

0.0616

Gnomad4 EAS

AF:

0.0226

Gnomad4 SAS

AF:

0.0541

Gnomad4 FIN

AF:

0.00518

Gnomad4 NFE

AF:

0.0411

Gnomad4 OTH

AF:

0.145

Alfa

AF:

0.0645

Hom.:

2361

Bravo

AF:

0.186

TwinsUK

AF:

0.0361

AC:

134

ALSPAC

AF:

0.0376

AC:

145

ESP6500AA

AF:

0.478

AC:

2105

ESP6500EA

AF:

0.0465

AC:

400

ExAC

AF:

0.0802

AC:

9739

Asia WGS

AF:

0.0660

AC:

231

AN:

3478

EpiCase

AF:

0.0498

EpiControl

AF:

0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:3

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	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 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. -

Retinitis Pigmentosa, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Stargardt Disease, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

ABCA4-related disorder

Benign:1

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cone-Rod Dystrophy, Recessive

Benign:1

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

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

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

1.7

DANN

Benign

0.69

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.048

T;T

MetaRNN

Benign

0.00012

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.34

.;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.99

.;N

REVEL

Benign

0.20

Sift

Benign

0.13

.;T

Sift4G

Benign

0.089

T;D

Polyphen

0.0

.;B

Vest4

0.026

MPC

0.099

ClinPred

0.0043

GERP RS

-2.0

Varity_R

0.085

gMVP

0.22

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

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