chr1-94056692-C-T

Position:

chr1-94056692-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000370225.4(ABCA4):c.2291G>A(p.Cys764Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C764F) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ABCA4
ENST00000370225.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 6.08

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 Pathogenic. Variant got 18 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, 7 uncertain in ENST00000370225.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94056692-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3006375.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 1-94056692-C-T is Pathogenic according to our data. Variant chr1-94056692-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94056692-C-T is described in Lovd as [Pathogenic]. Variant chr1-94056692-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94056692-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.2291G>A	p.Cys764Tyr	missense_variant	15/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1 linkuse as main transcript	c.2161-1377G>A		intron_variant			XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.2291G>A	p.Cys764Tyr	missense_variant	15/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000649773.1 linkuse as main transcript	c.2161-1377G>A		intron_variant				ENSP00000496882

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2024	Published functional studies suggest this variant results in mild impairment of ABCA4 expression and functional properties, however additional studies are needed to validate the functional effect of this variant (PMID: 33375396); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10958763, 31964843, 28118664, 32531858, 33546218, 33375396) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 764 of the ABCA4 protein (p.Cys764Tyr). This variant is present in population databases (rs61749428, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive Stargardt disease (PMID: 10958763, 28118664, 33546218). ClinVar contains an entry for this variant (Variation ID: 99123). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -

Severe early-childhood-onset retinal dystrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 11, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-9.6

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.96

MutPred

0.81

Gain of glycosylation at S765 (P = 0.0746);

MVP

0.99

MPC

0.60

ClinPred

1.0

GERP RS

5.7

Varity_R

0.99

gMVP

0.86

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