rs61754034

Positions:

chr1-94044699-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000350.3(ABCA4):c.2964C>T(p.Leu988=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,614,138 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 43 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 48 hom. )

Consequence

ABCA4
NM_000350.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 0.236

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 1-94044699-G-A is Benign according to our data. Variant chr1-94044699-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 99179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.236 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1999/152248) while in subpopulation AFR AF= 0.045 (1868/41534). AF 95% confidence interval is 0.0433. There are 43 homozygotes in gnomad4. There are 924 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.2964C>T	p.Leu988=	synonymous_variant	20/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1 linkuse as main transcript	c.2742C>T	p.Leu914=	synonymous_variant	19/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.2964C>T	p.Leu988=	synonymous_variant	20/50	1	NM_000350.3	ENSP00000359245	P1

Frequencies

GnomAD3 genomes

AF:

0.0131

AC:

1990

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0448

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.0124

GnomAD3 exomes

AF:

0.00375

AC:

942

AN:

251494

Hom.:

AF XY:

0.00297

AC XY:

404

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0490

Gnomad AMR exome

AF:

0.00254

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00166

AC:

2424

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1082

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0512

Gnomad4 AMR exome

AF:

0.00304

Gnomad4 ASJ exome

AF:

0.000497

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000195

Gnomad4 OTH exome

AF:

0.00454

GnomAD4 genome

AF:

0.0131

AC:

1999

AN:

152248

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

924

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0450

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0294

Hom.:

2363

Bravo

AF:

0.0151

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 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. -

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

BayesDel_noAF

Benign

-0.48

CADD

Benign

9.3

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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