rs61754024

chr1-94062586-A-Cchr1-94062586-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 5P and 6B. PM1 PM5 PP3 BP4_Moderate BS2

The NM_000350.3(ABCA4):c.1928T>G(p.Val643Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,613,566 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V643M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7 B:1 O:1
• Conservation: PhyloP100: 9.32

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94062587-C-T is described in Lovd as [Likely_pathogenic].
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.08142775).
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.1928T>G	p.Val643Gly	missense_variant	13/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.1928T>G	p.Val643Gly	missense_variant	13/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.1928T>G	p.Val643Gly	missense_variant	13/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.1928T>G	p.Val643Gly	missense_variant	13/19

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152046 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00155 AC: 389 AN: 251136 Hom.: 1 AF XY: 0.00161 AC XY: 219 AN XY: 135716

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00303

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00265 AC: 3880 AN: 1461404 Hom.: 7 Cov.: 37 AF XY: 0.00257 AC XY: 1868 AN XY: 727000

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.00336

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152162 Hom.: 2 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74402

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00252 Hom.: 0

Bravo AF: 0.00165

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00134 AC: 163

EpiCase AF: 0.00191

EpiControl AF: 0.00279

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ABCA4: PM3, PM2:Supporting -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2023	Identified previously in other individual with features of an ABCA4-related disorder; however, the variant was either reported in the heterozygous state, or was seen with a second ABCA4 variant, phase unknown, whose pathogenicity was not established (Allikmets et al., 1997; Sciezynska et al., 2015; Rosenberg et al., 2007; Birtel et al., 2018; Sergouniotis et al., 2016); 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: 20981092, 27628848, 24265693, 17982420, 26593885, 29555955, 34426522, Scott2022[CaseReport], 34513887, 31429209, 32531858, 9295268) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	The ABCA4 c.1928T>G; p.Val643Gly variant (rs61754024) is reported in the medical literature in individuals with retinopathy in the heterozygous state without an additional pathogenic ABCA4 variant (Birtel 2018, Rosenberg 2007, Scienzynska 2016) and was originally described at a similar frequency in affected and unaffected individuals (Allikmets 1997). The variant is reported in the ClinVar database (Variation ID: 99102) and in the European (non-Finnish) population with an overall allele frequency of 0.3% (389/128892 alleles including 1 homozygote) in the Genome Aggregation Database. The valine at this position is highly conserve but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the variant is uncertain at this time. References: Allikmets R et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997 Sep 19;277(5333):1805-7. Birtel J et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018 Mar 19;8(1):4824 Rosenberg T et al. N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population. Mol Vis. 2007 Oct 17;13:1962-9. Sciezynska A et al. Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe. Exp Eye Res. 2016 Apr;145:93-99. -
not provided, no classification provided	literature only	Retina International	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 01, 2016	- -

Severe early-childhood-onset retinal dystrophy Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The ABCA4 c.1928T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

ABCA4-Related Disorders Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Feb 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.081	T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.21	B;.
Vest4		0.67
MVP		0.99
MPC		0.53
ClinPred		0.096	T
GERP RS		5.0
Varity_R		0.94
gMVP		0.93

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: rs61754024; hg19: chr1-94528142;