rs3112831

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBA1

The NM_000350.3(ABCA4):c.1268A>G(p.His423Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,610,992 control chromosomes in the GnomAD database, including 72,755 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H423P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.26 ( 5454 hom., cov: 28)

Exomes 𝑓: 0.30 ( 67301 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 2.40

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 -16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94078679-G-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.035622448).

BP6

Variant 1-94078678-T-C is Benign according to our data. Variant chr1-94078678-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 99040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94078678-T-C is described in Lovd as [Benign]. Variant chr1-94078678-T-C is described in Lovd as [Pathogenic]. Variant chr1-94078678-T-C is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.314 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.1268A>G	p.His423Arg	missense_variant	10/50	ENST00000370225.4	NP_000341.2	P78363Q6AI28
ABCA4	XM_047416704.1 linkuse as main transcript	c.1268A>G	p.His423Arg	missense_variant	10/49
LOC124904222	XR_007066231.1 linkuse as main transcript	n.203-5051T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.1268A>G	p.His423Arg	missense_variant	10/50	1	NM_000350.3	ENSP00000359245.3		P78363
ABCA4	ENST00000649773.1 linkuse as main transcript	c.1268A>G	p.His423Arg	missense_variant	10/19			ENSP00000496882.1		A0A3B3IRV8

Frequencies

GnomAD3 genomes

AF:

0.258

AC:

39029

AN:

151382

Hom.:

5443

Cov.:

show subpopulations

Gnomad AFR

AF:

0.163

Gnomad AMI

AF:

0.239

Gnomad AMR

AF:

0.279

Gnomad ASJ

AF:

0.250

Gnomad EAS

AF:

0.260

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.265

GnomAD3 exomes

AF:

0.255

AC:

64225

AN:

251484

Hom.:

8697

AF XY:

0.254

AC XY:

34526

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.162

Gnomad AMR exome

AF:

0.219

Gnomad ASJ exome

AF:

0.234

Gnomad EAS exome

AF:

0.246

Gnomad SAS exome

AF:

0.165

Gnomad FIN exome

AF:

0.250

Gnomad NFE exome

AF:

0.308

Gnomad OTH exome

AF:

0.271

GnomAD4 exome

AF:

0.299

AC:

435950

AN:

1459492

Hom.:

67301

Cov.:

AF XY:

0.294

AC XY:

213617

AN XY:

726128

show subpopulations

Gnomad4 AFR exome

AF:

0.162

Gnomad4 AMR exome

AF:

0.227

Gnomad4 ASJ exome

AF:

0.237

Gnomad4 EAS exome

AF:

0.254

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.253

Gnomad4 NFE exome

AF:

0.323

Gnomad4 OTH exome

AF:

0.277

GnomAD4 genome

AF:

0.258

AC:

39076

AN:

151500

Hom.:

5454

Cov.:

AF XY:

0.254

AC XY:

18812

AN XY:

73986

show subpopulations

Gnomad4 AFR

AF:

0.164

Gnomad4 AMR

AF:

0.280

Gnomad4 ASJ

AF:

0.250

Gnomad4 EAS

AF:

0.260

Gnomad4 SAS

AF:

0.175

Gnomad4 FIN

AF:

0.254

Gnomad4 NFE

AF:

0.318

Gnomad4 OTH

AF:

0.265

Alfa

AF:

0.300

Hom.:

12773

Bravo

AF:

0.256

TwinsUK

AF:

0.328

AC:

1216

ALSPAC

AF:

0.304

AC:

1170

ESP6500AA

AF:

0.165

AC:

729

ESP6500EA

AF:

0.309

AC:

2661

ExAC

AF:

0.255

AC:

30988

Asia WGS

AF:

0.236

AC:

819

AN:

3478

EpiCase

AF:

0.303

EpiControl

AF:

0.304

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 31, 2016	- -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2012	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	Eurofins Ntd Llc (ga)	May 19, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

- -

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

0.048

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.27

CADD

Benign

4.8

DANN

Benign

0.92

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.077

T;T

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-2.5

N;.

PrimateAI

Benign

0.41

PROVEAN

Benign

2.1

N;.

REVEL

Uncertain

0.29

Sift

Benign

0.36

T;.

Sift4G

Benign

0.28

T;.

Polyphen

0.0

B;.

Vest4

0.038

MPC

0.10

ClinPred

0.014

GERP RS

5.5

Varity_R

0.076

gMVP

0.64

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