1-94031046-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000350.3(ABCA4):c.4203C>A(p.Pro1401=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0309 in 1,614,092 control chromosomes in the GnomAD database, including 920 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1401P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (47 hom., cov: 32)
  • Exomes 𝑓: 0.032 (873 hom.)
• Consequence: ABCA4 NM_000350.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -2.02

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=-0.76).
• BP6: Variant 1-94031046-G-T is Benign according to our data. Variant chr1-94031046-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 99258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94031046-G-T is described in Lovd as [Benign]. Variant chr1-94031046-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0217 (3310/152290) while in subpopulation NFE AF= 0.0352 (2396/68030). AF 95% confidence interval is 0.034. There are 47 homozygotes in gnomad4. There are 1531 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.4203C>A	p.Pro1401=	synonymous_variant	28/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.3981C>A	p.Pro1327=	synonymous_variant	27/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.4203C>A	p.Pro1401=	synonymous_variant	28/50	1	NM_000350.3	P1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3312 AN: 152172 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00889

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0235 AC: 5912 AN: 251302 Hom.: 99 AF XY: 0.0234 AC XY: 3181 AN XY: 135848

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00908

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0369

Gnomad OTH exome AF: 0.0272

GnomAD4 exome AF: 0.0319 AC: 46640 AN: 1461802 Hom.: 873 Cov.: 32 AF XY: 0.0312 AC XY: 22722 AN XY: 727198

Gnomad4 AFR exome AF: 0.00412

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.00991

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00964

Gnomad4 FIN exome AF: 0.0312

Gnomad4 NFE exome AF: 0.0374

Gnomad4 OTH exome AF: 0.0251

GnomAD4 genome AF: 0.0217 AC: 3310 AN: 152290 Hom.: 47 Cov.: 32 AF XY: 0.0206 AC XY: 1531 AN XY: 74466

Gnomad4 AFR AF: 0.00590

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00890

Gnomad4 FIN AF: 0.0311

Gnomad4 NFE AF: 0.0352

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0266 Hom.: 71

Bravo AF: 0.0196

EpiCase AF: 0.0324

EpiControl AF: 0.0328

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 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. -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -

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	-0.76
Cadd	Benign	1.6
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1801666; hg19: chr1-94496602;