rs61750566

Positions:

• chr1-94019615-GGT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000350.3(ABCA4):​c.5161_5162del​(p.Thr1721HisfsTer65) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ABCA4 NM_000350.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 0.694

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-94019615-GGT-G is Pathogenic according to our data. Variant chr1-94019615-GGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 99349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94019615-GGT-G is described in Lovd as [Pathogenic]. Variant chr1-94019615-GGT-G is described in Lovd as [Likely_pathogenic]. Variant chr1-94019615-GGT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.5161_5162del	p.Thr1721HisfsTer65	frameshift_variant	36/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.4939_4940del	p.Thr1647HisfsTer65	frameshift_variant	35/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.5161_5162del	p.Thr1721HisfsTer65	frameshift_variant	36/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000460514.1	n.655_656del		non_coding_transcript_exon_variant	7/7	5
ABCA4	ENST00000470771.1	n.271_272del		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000817 AC: 2 AN: 244776 Hom.: 0 AF XY: 0.00000757 AC XY: 1 AN XY: 132028

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458340 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 724960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3 Other:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 29, 2022	This sequence change creates a premature translational stop signal (p.Thr1721Hisfs*65) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). This variant is present in population databases (rs61750566, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Stargardt Disease (PMID: 10090887, 25312043, 25444351, 28041643, 29925512). This variant is also known as 5161delAC. ClinVar contains an entry for this variant (Variation ID: 99349). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
not provided, flagged submission	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2015	The c.5161_5162delAC deletion in the ABCA4 gene has been reported previously in association with Stargardt disease (Maugeri et al., 1999; Papaioannou et al., 2000; Briggs et al., 2001). The deletion causes a frameshift starting with codon Threonine 1721, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 65 of the new reading frame, denoted p.Thr1721HisfsX65. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we interpret this variant as pathogenic. -
not provided, no classification provided	literature only	Retina International	-	- -

Severe early-childhood-onset retinal dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs61750566; hg19: chr1-94485171;