1-94098927-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1 PM5 BP4_Strong BP6 BA1

The NM_000350.3(ABCA4):c.635G>A(p.Arg212His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 1,613,470 control chromosomes in the GnomAD database, including 1,401 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. R212C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.049 (184 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1217 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12 O:1
• Conservation: PhyloP100: 3.20

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 -9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94098928-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.017632037).
• BP6: Variant 1-94098927-C-T is Benign according to our data. Variant chr1-94098927-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 99454.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=5, not_provided=1, Uncertain_significance=1}. Variant chr1-94098927-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94098927-C-T is described in Lovd as [Likely_benign]. Variant chr1-94098927-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.635G>A	p.Arg212His	missense_variant	6/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.635G>A	p.Arg212His	missense_variant	6/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.635G>A	p.Arg212His	missense_variant	6/50	1	NM_000350.3	P1
ABCA4	ENST00000649773.1	c.635G>A	p.Arg212His	missense_variant	6/19

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7389 AN: 152150 Hom.: 183 Cov.: 33

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0477

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.0581

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0379

Gnomad OTH AF: 0.0397

GnomAD3 exomes AF: 0.0411 AC: 10284 AN: 250264 Hom.: 256 AF XY: 0.0390 AC XY: 5269 AN XY: 135254

Gnomad AFR exome AF: 0.0723

Gnomad AMR exome AF: 0.0413

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.0614

Gnomad SAS exome AF: 0.0243

Gnomad FIN exome AF: 0.0610

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0399

GnomAD4 exome AF: 0.0388 AC: 56713 AN: 1461202 Hom.: 1217 Cov.: 32 AF XY: 0.0378 AC XY: 27470 AN XY: 726830

Gnomad4 AFR exome AF: 0.0710

Gnomad4 AMR exome AF: 0.0406

Gnomad4 ASJ exome AF: 0.0315

Gnomad4 EAS exome AF: 0.0615

Gnomad4 SAS exome AF: 0.0225

Gnomad4 FIN exome AF: 0.0607

Gnomad4 NFE exome AF: 0.0371

Gnomad4 OTH exome AF: 0.0434

GnomAD4 genome AF: 0.0486 AC: 7400 AN: 152268 Hom.: 184 Cov.: 33 AF XY: 0.0486 AC XY: 3617 AN XY: 74456

Gnomad4 AFR AF: 0.0683

Gnomad4 AMR AF: 0.0477

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.0582

Gnomad4 SAS AF: 0.0290

Gnomad4 FIN AF: 0.0544

Gnomad4 NFE AF: 0.0379

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0364 Hom.: 164

Bravo AF: 0.0476

TwinsUK AF: 0.0410 AC: 152

ALSPAC AF: 0.0384 AC: 148

ESP6500AA AF: 0.0706 AC: 311

ESP6500EA AF: 0.0341 AC: 293

ExAC AF: 0.0403 AC: 4898

Asia WGS AF: 0.0530 AC: 187 AN: 3478

EpiCase AF: 0.0364

EpiControl AF: 0.0359

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Stargardt Disease, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

ABCA4-related disorder Benign:1

Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cone-Rod Dystrophy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Macular degeneration Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	22
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;D
MetaRNN	Benign	0.018	T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	0.0019	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.72
Sift	Benign	0.061	T;.
Sift4G	Uncertain	0.049	D;.
Polyphen		1.0	D;.
Vest4		0.42
MPC		0.12
ClinPred		0.041	T
GERP RS		4.0
Varity_R		0.058
gMVP		0.85

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: rs6657239; hg19: chr1-94564483; COSMIC: COSV64673474;