1-94098927-C-T

Position:

chr1-94098927-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1PM5BP4_StrongBP6BA1

The NM_000350.3(ABCA4):c.635G>A(p.Arg212His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,470 control chromosomes in the GnomAD database, including 1,401 homozygotes. 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. R212C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.049 ( 184 hom., cov: 33)

Exomes 𝑓: 0.039 ( 1217 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13O:1

Conservation

PhyloP100: 3.20

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:

ABCA4 (HGNC:):

ABCA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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 NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94098928-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.017632037).

BP6

Variant 1-94098927-C-T is Benign according to our data. Variant chr1-94098927-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99454.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, not_provided=1, Benign=5}. Variant chr1-94098927-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94098927-C-T is described in Lovd as [Likely_benign]. Variant chr1-94098927-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0662 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.635G>A	p.Arg212His	missense_variant	6/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.635G>A	p.Arg212His	missense_variant	6/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.635G>A	p.Arg212His	missense_variant	6/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000649773.1 linkuse as main transcript	c.635G>A	p.Arg212His	missense_variant	6/19			ENSP00000496882.1		A0A3B3IRV8

Frequencies

GnomAD3 genomes

AF:

0.0486

AC:

7389

AN:

152150

Hom.:

183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0682

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0477

Gnomad ASJ

AF:

0.0331

Gnomad EAS

AF:

0.0581

Gnomad SAS

AF:

0.0292

Gnomad FIN

AF:

0.0544

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0379

Gnomad OTH

AF:

0.0397

GnomAD3 exomes

AF:

0.0411

AC:

10284

AN:

250264

Hom.:

256

AF XY:

0.0390

AC XY:

5269

AN XY:

135254

show subpopulations

Gnomad AFR exome

AF:

0.0723

Gnomad AMR exome

AF:

0.0413

Gnomad ASJ exome

AF:

0.0301

Gnomad EAS exome

AF:

0.0614

Gnomad SAS exome

AF:

0.0243

Gnomad FIN exome

AF:

0.0610

Gnomad NFE exome

AF:

0.0352

Gnomad OTH exome

AF:

0.0399

GnomAD4 exome

AF:

0.0388

AC:

56713

AN:

1461202

Hom.:

1217

Cov.:

AF XY:

0.0378

AC XY:

27470

AN XY:

726830

show subpopulations

Gnomad4 AFR exome

AF:

0.0710

Gnomad4 AMR exome

AF:

0.0406

Gnomad4 ASJ exome

AF:

0.0315

Gnomad4 EAS exome

AF:

0.0615

Gnomad4 SAS exome

AF:

0.0225

Gnomad4 FIN exome

AF:

0.0607

Gnomad4 NFE exome

AF:

0.0371

Gnomad4 OTH exome

AF:

0.0434

GnomAD4 genome

AF:

0.0486

AC:

7400

AN:

152268

Hom.:

184

Cov.:

AF XY:

0.0486

AC XY:

3617

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0683

Gnomad4 AMR

AF:

0.0477

Gnomad4 ASJ

AF:

0.0331

Gnomad4 EAS

AF:

0.0582

Gnomad4 SAS

AF:

0.0290

Gnomad4 FIN

AF:

0.0544

Gnomad4 NFE

AF:

0.0379

Gnomad4 OTH

AF:

0.0402

Alfa

AF:

0.0364

Hom.:

164

Bravo

AF:

0.0476

TwinsUK

AF:

0.0410

AC:

152

ALSPAC

AF:

0.0384

AC:

148

ESP6500AA

AF:

0.0706

AC:

311

ESP6500EA

AF:

0.0341

AC:

293

ExAC

AF:

0.0403

AC:

4898

Asia WGS

AF:

0.0530

AC:

187

AN:

3478

EpiCase

AF:

0.0364

EpiControl

AF:

0.0359

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:3Other: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	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

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

- -

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

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;D

MetaRNN

Benign

0.018

T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.2

N;.

REVEL

Pathogenic

0.72

Sift

Benign

0.061

T;.

Sift4G

Uncertain

0.049

D;.

Polyphen

1.0

D;.

Vest4

0.42

MPC

0.12

ClinPred

0.041

GERP RS

4.0

Varity_R

0.058

gMVP

0.85

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