1-94103130-C-T

Position:

• chr1-94103130-C-T

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.455G>A​(p.Arg152Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00427 in 1,613,942 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R152R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (25 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:7 O:2
• Conservation: PhyloP100: 1.22

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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000350.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010893583).
• 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.455G>A	p.Arg152Gln	missense_variant	5/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.455G>A	p.Arg152Gln	missense_variant	5/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.455G>A	p.Arg152Gln	missense_variant	5/50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.455G>A	p.Arg152Gln	missense_variant	5/19			ENSP00000496882.1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152150 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00259 AC: 651 AN: 251232 Hom.: 2 AF XY: 0.00258 AC XY: 351 AN XY: 135794

Gnomad AFR exome AF: 0.000863

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00314

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00370

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00442 AC: 6461 AN: 1461674 Hom.: 25 Cov.: 32 AF XY: 0.00434 AC XY: 3156 AN XY: 727160

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00302

Gnomad4 FIN exome AF: 0.000787

Gnomad4 NFE exome AF: 0.00516

Gnomad4 OTH exome AF: 0.00459

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152268 Hom.: 3 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74452

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00431

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00387 Hom.: 0

Bravo AF: 0.00298

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00239 AC: 290

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:7 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5 Other:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ABCA4 p.Arg152Gln variant was identified in 5 of 958 proband chromosomes (frequency: 0.005) from individuals or families with Stargardt Disease and Age-related Macular Degeneration and was present in 3 of 440 control chromosomes (frequency: 0.0068) from healthy individuals (Rivera_2000_PMID:10958763; Schulz_2017_PMID:28118664). The variant was also identified in dbSNP (ID: rs62646862), LOVD 3.0 and in ClinVar (classified as likely benign by EGL Genetics, GeneDx and ARUP Laboratories and as likely pathogenic by the University Regensberg Institute of Human Genetics). The variant was not identified in Cosmic. The variant was identified in control databases in 651 of 251232 chromosomes (2 homozygous) at a frequency of 0.002591 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 420 of 113574 chromosomes (freq: 0.003698), South Asian in 96 of 30610 chromosomes (freq: 0.003136), Other in 18 of 6136 chromosomes (freq: 0.002934), Latino in 86 of 34578 chromosomes (freq: 0.002487), African in 14 of 16230 chromosomes (freq: 0.000863) and European (Finnish) in 17 of 21646 chromosomes (freq: 0.000785); it was not observed in the Ashkenazi Jewish and East Asian populations. The p.Arg152 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ABCA4: BP4, BS2 -
not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2020	This variant is associated with the following publications: (PMID: 11702214, 23143460, 22264887, 11385708, 26593885, 14517951, 15192030, 25444351, 28118664, 22328824, 15161829, 10958763, 23953153, 16917483, 26764160, 28898540, 29925512, 30093795, 31456290) -

Stargardt disease Pathogenic:1 Other:1

Likely pathogenic, flagged submission	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 06-25-2018 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

ABCA4-related disorder Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 28, 2024	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
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. -

Severe early-childhood-onset retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

The ABCA4 c.455G>A 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: BS1, PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 01, 2022

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.1	N;.
REVEL	Uncertain	0.43
Sift	Benign	0.12	T;.
Sift4G	Benign	0.22	T;.
Polyphen		0.012	B;.
Vest4		0.16
MVP		0.88
MPC		0.098
ClinPred		0.031	T
GERP RS		2.6
Varity_R		0.058
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62646862; hg19: chr1-94568686; COSMIC: COSV104677865;