1-94077712-C-T

Position:

chr1-94077712-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM5BP4_StrongBS2

The NM_000350.3(ABCA4):c.1532G>A(p.Arg511His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000801 in 1,613,274 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. R511C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 8 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:6O:1

Conservation

PhyloP100: 0.380

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:

LOC124904222 (HGNC:):

LOC124904222 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a helix (size 18) in uniprot entity ABCA4_HUMAN there are 25 pathogenic changes around while only 1 benign (96%) in NM_000350.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94077713-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.01130414).

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ABCA4	NM_000350.3 linkuse as main transcript	c.1532G>A	p.Arg511His	missense_variant	11/50	ENST00000370225.4	NP_000341.2
LOC124904222	XR_007066231.1 linkuse as main transcript	n.203-6017C>T		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1 linkuse as main transcript	c.1532G>A	p.Arg511His	missense_variant	11/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.1532G>A	p.Arg511His	missense_variant	11/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000649773.1 linkuse as main transcript	c.1532G>A	p.Arg511His	missense_variant	11/19			ENSP00000496882

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000778

AC:

195

AN:

250676

Hom.:

AF XY:

0.00102

AC XY:

138

AN XY:

135440

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.00404

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000521

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000836

AC:

1221

AN:

1461042

Hom.:

Cov.:

AF XY:

0.000973

AC XY:

707

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00466

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000677

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.000473

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000459

Hom.:

Bravo

AF:

0.000408

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000799

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000764

EpiControl

AF:

0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	ABCA4: PM5, BP4 -

Retinal dystrophy

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 05, 2019	- -

ABCA4-related disorder

Uncertain:1Benign:1

Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 30, 2022	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Severe early-childhood-onset retinal dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

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

- -

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

- -

Stargardt disease

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpretted as Uncertain significance and reported on 12/28/2017 by GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.47

MutationAssessor

Benign

0.93

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

N;.

REVEL

Uncertain

0.34

Sift

Benign

0.18

T;.

Sift4G

Benign

0.26

T;.

Polyphen

0.0020

B;.

Vest4

0.28

MVP

0.88

MPC

0.11

ClinPred

0.016

GERP RS

2.4

Varity_R

0.096

gMVP

0.74

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