1-94047046-C-T

Position:

chr1-94047046-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM5PP5BP4

The NM_000350.3(ABCA4):c.2791G>A(p.Val931Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V931L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:1O:1

Conservation

PhyloP100: 1.44

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94047045-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2777907.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 1-94047046-C-T is Pathogenic according to our data. Variant chr1-94047046-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7880.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Pathogenic=4, Likely_pathogenic=3, Uncertain_significance=1}. Variant chr1-94047046-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94047046-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.023732096). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.2791G>A	p.Val931Met	missense_variant	19/50	ENST00000370225.4
ABCA4	XM_047416704.1 linkuse as main transcript	c.2569G>A	p.Val857Met	missense_variant	18/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.2791G>A	p.Val931Met	missense_variant	19/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1 linkuse as main transcript	c.2569G>A	p.Val857Met	missense_variant	18/19

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00427

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.00191

GnomAD3 exomes

AF:

0.000386

AC:

AN:

251362

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.00443

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000166

AC:

242

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00412

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.000778

GnomAD4 genome

AF:

0.00127

AC:

194

AN:

152236

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00431

Gnomad4 AMR

AF:

0.000654

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:

0.00189

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.00144

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000486

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 931 of the ABCA4 protein (p.Val931Met). This variant is present in population databases (rs58331765, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Stargardt disease (PMID: 9054934, 9973280, 19365591, 23755871, 28430335, 29114839, 30093795). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7880). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22264887, 27884173, 19365591, 9973280, 31456290, 9054934, 23755871, 30093795, 32619608, 24123366, 18977788, 35119454, 31816670, 27535533, 37498587, 35120629, 31964843, 32307445, 36011402) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 2016	- -
not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 18, 2023	The p.Val931Met variant in ABCA4 has been reported in the homozygous and compound heterozygous state in >10 individuals with Stargardt disease, however it was also found with other variants in ABCA4 in some affected individuals that could potentially explain their disease. This variant segregated with disease in 1 affected homozygous relative from a consanguineous family (Allikmets 1997 PMID: 9054934, Lewis 1999 PMID: 9973280, Maia-Lopes 2009 PMID: 19365591, Fujinami 2013 PMID: 23769331, Riveiro-Alvarez 2013 PMID: 23755871, Vallim-Salles 2017 PMID: 29114839, Pozo-Valero 2020 PMID: 32619608). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 7880). It has also been identified in 0.4% (177/41416) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_Strong. -

Severe early-childhood-onset retinal dystrophy

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1997	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cone-rod dystrophy 3 (MIM#604116), fundus flavimaculatus (MIM#248200), early-onset severe retinal dystrophy (MIM#248200), retinitis pigmentosa 19 (MIM#601718) and Stargardt disease 1 (MIM#248200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 190 heterozygotes, 0 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Val931Ala)) (7 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ABC transporter domain 1 (UniProt). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. The p.(Val931Leu) variant has been classified as both Pathogenic and Variant of Uncertain Significance, with limited or no evidence for their respective classification (ClinVar; PMID: 31213501). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals with Stargardt disease; however it should be noted that some studies have also classified this variant as benign or likely benign (ClinVar; PMIDs: 9054934, 23755871, 23755871, 30093795, 23769331, 25082829, 31456290, 32619608). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000350.2(ABCA4):c.4981del; p.(Leu1661*)) in a recessive disease. Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

Aug 08, 2022

- -

ABCA4-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2024

The ABCA4 c.2791G>A variant is predicted to result in the amino acid substitution p.Val931Met. This variant has been reported in the compound heterozygous state many times in individuals with retinal dystrophy (see for examples Allikmets et al. 1997. PubMed ID: 9054934; Salles et al. 2018. PubMed ID: 30093795; Del Pozo-Valero et al. 2020. PubMed ID: 32619608; Table S2 in Sharon et al. 2020. PubMed ID: 31456290). This variant is reported in 0.44% of alleles in individuals of African descent in gnomAD, indicating it is relatively common. This variant has been listed as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/7880/). Given the evidence, we interpret this variant as likely pathogenic. -

Retinitis pigmentosa 19

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Jan 03, 2022

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007880, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000865894, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.664, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 19 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000474, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 12, 2019

- -

Stargardt disease

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

D;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.024

T;T

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

0.99

A;A

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.0

N;.

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

0.76

P;.

Vest4

0.52

MVP

0.91

MPC

0.36

ClinPred

0.028

GERP RS

5.6

Varity_R

0.19

gMVP

0.81

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