rs113106943

chr1-94021848-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000350.3(ABCA4):c.4771G>A(p.Gly1591Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,614,112 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. G1591E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (14 hom.)
• Consequence: ABCA4 NM_000350.3 missense, splice_region
• Scores: Splicing: ADA: 0.0005641
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:6
• Conservation: PhyloP100: 3.51

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 -2 ACMG points.

• PM1: In a hotspot region, there are 4 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=0.008526325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.4771G>A	p.Gly1591Arg	missense_variant, splice_region_variant	33/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.4549G>A	p.Gly1517Arg	missense_variant, splice_region_variant	32/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.4771G>A	p.Gly1591Arg	missense_variant, splice_region_variant	33/50	1	NM_000350.3	P1
ABCA4	ENST00000460514.1	n.265G>A		splice_region_variant, non_coding_transcript_exon_variant	4/7	5

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 352 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00242 AC: 609 AN: 251416 Hom.: 0 AF XY: 0.00230 AC XY: 313 AN XY: 135906

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00248 AC: 3629 AN: 1461832 Hom.: 14 Cov.: 32 AF XY: 0.00254 AC XY: 1844 AN XY: 727224

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00273

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74450

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00395 Hom.: 1

Bravo AF: 0.00180

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00261 AC: 317

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2021	Identified as a single heterozygous variant in an individual with retinitis pigmentosa who had a different genetic etiology for the phenotype (Eisenberger et al., 2013); This variant is associated with the following publications: (PMID: 28044389, 29925512, 32581362, 24265693, 25346251, 26720470, 28224992, 29555955, 29854428, 28118664, 28041643) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -

Retinal dystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 19, 2019	- -

Severe early-childhood-onset retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jan 01, 2016

- -

Cone dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

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

- -

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	0.21
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Benign	0.94
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	0.043
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	0.55	T;T
Polyphen		0.97	.;D
Vest4		0.45
MutPred		0.45		.;Gain of solvent accessibility (P = 0.0037);
MVP		0.90
MPC		0.36
ClinPred		0.034	T
GERP RS		4.3
Varity_R		0.12
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.010		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: rs113106943; hg19: chr1-94487404; COSMIC: COSV64671271; COSMIC: COSV64671271;