rs61754022

Positions:

• chr1-94062803-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000350.3(ABCA4):​c.1761-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,585,642 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.017 (243 hom.)
• Consequence: ABCA4 NM_000350.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.0770

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-94062803-C-T is Benign according to our data. Variant chr1-94062803-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 99078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1848/152240) while in subpopulation NFE AF= 0.0194 (1320/68014). AF 95% confidence interval is 0.0185. There are 12 homozygotes in gnomad4. There are 879 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.1761-50G>A		intron_variant		ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.1761-50G>A		intron_variant			XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.1761-50G>A		intron_variant		1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000649773.1	c.1761-50G>A		intron_variant				ENSP00000496882

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1847 AN: 152122 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00788

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0194

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0141 AC: 3236 AN: 228846 Hom.: 21 AF XY: 0.0144 AC XY: 1771 AN XY: 123364

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0259

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00868

Gnomad FIN exome AF: 0.00898

Gnomad NFE exome AF: 0.0202

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0168 AC: 24061 AN: 1433402 Hom.: 243 Cov.: 28 AF XY: 0.0168 AC XY: 11999 AN XY: 712904

Gnomad4 AFR exome AF: 0.00240

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.0244

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.00957

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.0121 AC: 1848 AN: 152240 Hom.: 12 Cov.: 32 AF XY: 0.0118 AC XY: 879 AN XY: 74432

Gnomad4 AFR AF: 0.00310

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00789

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.0194

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0187 Hom.: 3

Bravo AF: 0.0117

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Retina International	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.80

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: rs61754022; hg19: chr1-94528359; COSMIC: COSV64676956; COSMIC: COSV64676956;