rs375179475

chr1-93996214-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000350.3(ABCA4):c.6730-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,582,074 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (2 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:3
• Conservation: PhyloP100: -0.0680

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.6730-19G>A		intron_variant		ENST00000370225.4
ABCA4	XM_047416704.1	c.6508-19G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.6730-19G>A		intron_variant		1	NM_000350.3	P1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152182 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000804 AC: 201 AN: 250088 Hom.: 2 AF XY: 0.000754 AC XY: 102 AN XY: 135240

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00685

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000704 AC: 1006 AN: 1429892 Hom.: 2 Cov.: 27 AF XY: 0.000705 AC XY: 503 AN XY: 713522

Gnomad4 AFR exome AF: 0.000156

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00748

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000620

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152182 Hom.: 1 Cov.: 33 AF XY: 0.000404 AC XY: 30 AN XY: 74348

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.000635

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2015	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	13
Dann	Benign	0.47

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: rs375179475; hg19: chr1-94461770;