rs61749435

Positions:

• chr1-94055152-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_000350.3(ABCA4):​c.2546T>C​(p.Val849Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000725 in 1,614,186 control chromosomes in the GnomAD database, including 7 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 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (4 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2 O:1
• Conservation: PhyloP100: 9.26

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 Likely_benign. Variant got -6 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, 9 uncertain in NM_000350.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0110659).
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.2546T>C	p.Val849Ala	missense_variant	16/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.2324T>C	p.Val775Ala	missense_variant	15/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.2546T>C	p.Val849Ala	missense_variant	16/50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.2324T>C	p.Val775Ala	missense_variant	15/19			ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152178 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00108 AC: 272 AN: 251412 Hom.: 3 AF XY: 0.000802 AC XY: 109 AN XY: 135872

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000432 AC: 631 AN: 1461890 Hom.: 4 Cov.: 31 AF XY: 0.000415 AC XY: 302 AN XY: 727246

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152296 Hom.: 3 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74462

Gnomad4 AFR AF: 0.0123

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000680 Hom.: 0

Bravo AF: 0.00417

ESP6500AA AF: 0.0123 AC: 54

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00133 AC: 162

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2019	This variant is associated with the following publications: (PMID: 11328725, 22264887, 25910913, 30215852, 29925512, 32619608, 15223829, 24011517, 14971589, 20935302, 25066811, 16917483, 14709597) -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 10, 2019	The ABCA4 c.2546T>C; p.Val849Ala variant (rs61749435) is reported in the literature in multiple individuals affected with Stargardt disease or related retinopathies, although these studies do not agree on the variant’s clinical significance (Cideciyan 2004, Fujinami 2019, Kersten 2018, Lee 2015, Thiadens 2012, Webster 2001). Several affected individuals with the p.Val849Ala variant carried an additional pathogenic variant (Fujinami 2019, Cideciyan 2004), although one individual was found with two other pathogenic ABCA4 variants that may have explained this individual’s disease (Lee 2015). The p.Val849Ala variant is found in the African population with an overall allele frequency of 1.3% (324/24946 alleles, including five homozygotes) in the Genome Aggregation Database. The valine at codon 849 is weakly conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the p.Val849Ala variant is uncertain at this time. References: Cideciyan AV et al. Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence. Hum Mol Genet. 2004 Mar 1;13(5):525-34. Fujinami K et al. Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. Br J Ophthalmol. 2019 Mar;103(3):390-397. Kersten E et al. Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration. Clin Genet. 2018 Dec;94(6):569-574. Lee K et al. High Diagnostic Yield of Whole Exome Sequencing in Participants With Retinal Dystrophies in a Clinical Ophthalmology Setting. Am J Ophthalmol. 2015 Aug;160(2):354-363.e9. Thiadens AA et al. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012 Apr;119(4):819-26. Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89. -

Retinal dystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Dec 07, 2017	- -

Severe early-childhood-onset retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Optic atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.
Eigen	Benign	-0.033
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.97	L;.
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.013	B;.
Vest4		0.45
MVP		0.93
MPC		0.14
ClinPred		0.059	T
GERP RS		5.4
Varity_R		0.26
gMVP		0.57

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: rs61749435; hg19: chr1-94520708;