rs62642575

Positions:

• chr1-94024978-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP5

The NM_000350.3(ABCA4):​c.4610C>T​(p.Thr1537Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1537T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2 O:1
• Conservation: PhyloP100: 7.96

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]

ABCA4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000350.3
• PP5: Variant 1-94024978-G-A is Pathogenic according to our data. Variant chr1-94024978-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99306.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, not_provided=1, Likely_pathogenic=2}. Variant chr1-94024978-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-94024978-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.4610C>T	p.Thr1537Met	missense_variant	31/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.4388C>T	p.Thr1463Met	missense_variant	30/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.4610C>T	p.Thr1537Met	missense_variant	31/50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000460514.1	n.104C>T		non_coding_transcript_exon_variant	2/7	5

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251474 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00152

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000680

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000850 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2022	Identified without a second ABCA4 variant in individuals with retinal dystrophy (Rivera et al., 2000; Weisschuh et al., 2020; Sun et al., 2021; Ng et al., 2022); Identified in the heterozygous state in patients with nonsyndromic orofacial clefting (Peng et al., 2016); Published functional studies suggest a damaging effect with approximately 60% lower ATPase activity and 60% lower phospholipid transport activity compared to wild type (Quazi et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24097981, 34426522, 27527345, 31630094, 32531858, 33846575, 33301772, 10958763, 28118664) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1537 of the ABCA4 protein (p.Thr1537Met). This variant is present in population databases (rs62642575, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of Stargardt disease (PMID: 28118664, 31630094, 33301772; Invitae). ClinVar contains an entry for this variant (Variation ID: 99306). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 24097981). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	Retina International	-	- -

Severe early-childhood-onset retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:24097981). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.93; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with ABCA4 related disorder (ClinVar ID: VCV000099306 / PMID: 10958763). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2020

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 05, 2019

The ABCA4 c.4610C>T, p.Thr1537Met variant (rs62642575) is reported in the medical literature in two individuals with Stargardt disease, but information on an additional pathogenic variant in these individuals was not provided (Rivera 2000, Schulz 2017). The variant is reported in the ClinVar database (Variation ID: 99306) and in the general population with an allele frequency of 0.01% (34/282866 alleles) in the Genome Aggregation Database. The amino acid at this position is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Cell culture experiments show this variant slightly reduces function of the protein. However, due to limited information, the clinical significance of the variant is uncertain at this time. References: Quazi F et al. Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants. J Biol Chem. 2013 Nov 29;288(48):34414-26. Rivera A et al. A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. Am J Hum Genet. 2000 Oct;67(4):800-13 Schulz HL et al. Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort-Impact of Selected Deep Intronic Variants and Common SNPs. Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):394-403. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.3	.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.87
MVP		1.0
MPC		0.47
ClinPred		0.53	D
GERP RS		5.1
Varity_R		0.54
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62642575; hg19: chr1-94490534; COSMIC: COSV64671438; COSMIC: COSV64671438;