rs4847281

chr1-94112992-T-Cchr1-94112992-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000350.3(ABCA4):c.141A>G(p.Pro47=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,613,766 control chromosomes in the GnomAD database, including 803,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74421 hom., cov: 31)
  • Exomes 𝑓: 1.0 (729056 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.25

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-94112992-T-C is Benign according to our data. Variant chr1-94112992-T-C is described in ClinVar as [Benign]. Clinvar id is 166618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.141A>G	p.Pro47=	synonymous_variant	2/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.141A>G	p.Pro47=	synonymous_variant	2/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.141A>G	p.Pro47=	synonymous_variant	2/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.141A>G	p.Pro47=	synonymous_variant	2/19

Frequencies

GnomAD3 genomes AF: 0.989 AC: 150416 AN: 152160 Hom.: 74372 Cov.: 31

Gnomad AFR AF: 0.960

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.991

GnomAD3 exomes AF: 0.997 AC: 250709 AN: 251442 Hom.: 124997 AF XY: 0.998 AC XY: 135595 AN XY: 135890

Gnomad AFR exome AF: 0.959

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 1.00

GnomAD4 exome AF: 0.999 AC: 1459772 AN: 1461488 Hom.: 729056 Cov.: 42 AF XY: 0.999 AC XY: 726343 AN XY: 727068

Gnomad4 AFR exome AF: 0.958

Gnomad4 AMR exome AF: 0.998

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.997

GnomAD4 genome AF: 0.988 AC: 150524 AN: 152278 Hom.: 74421 Cov.: 31 AF XY: 0.988 AC XY: 73599 AN XY: 74460

Gnomad4 AFR AF: 0.960

Gnomad4 AMR AF: 0.995

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.991

Alfa AF: 0.998 Hom.: 152304

Bravo AF: 0.987

Asia WGS AF: 0.996 AC: 3465 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 17, 2013

- -

Age related macular degeneration 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Severe early-childhood-onset retinal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Retinitis pigmentosa 19 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Cone-rod dystrophy 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.36
Dann	Benign	0.38

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

Other links and lift over

dbSNP: rs4847281; hg19: chr1-94578548;