chr1-94037200-G-A

Position:

chr1-94037200-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The ENST00000370225.4(ABCA4):c.3758C>T(p.Thr1253Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000243 in 1,614,066 control chromosomes in the GnomAD database, including 3 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. T1253K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

ABCA4
ENST00000370225.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3O:1

Conservation

PhyloP100: 2.75

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012099832).

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.3758C>T	p.Thr1253Met	missense_variant	25/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1 linkuse as main transcript	c.3536C>T	p.Thr1179Met	missense_variant	24/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.3758C>T	p.Thr1253Met	missense_variant	25/50	1	NM_000350.3	ENSP00000359245	P1

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00837

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000434

AC:

109

AN:

251346

Hom.:

AF XY:

0.000442

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00904

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000244

AC:

357

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

182

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00957

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000927

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.000795

GnomAD4 genome

AF:

0.000230

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00837

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000609

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
not provided, no classification provided	literature only	Retina International	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ABCA4 p.Thr1253Met variant was identified in 6 of 1414 proband chromosomes (frequency: 0.0042) from individuals or families with ABCA4-related conditions (Stargardt disease 1, autosomal recessive retinitis pigmentosa, cone-rod dystrophy), however this variant has often been found in cis with the pathogenic p.G1961E variant, therefore it is unclear how this variant contributes to disease (Burke_2012_PMID:22661473; Shroyer_2001_PMID:11726554; Rosenberg_2007_PMID:17982420; Valverde_2005_PMID:16917483; Cella_2009_PMID:19217903; Riveiro-Alvarez_2013_PMID:23755871). The variant was identified in dbSNP (ID: rs61752424) and ClinVar (classified as likely benign by GeneDx, likely pathogenic by Institute of Human Genetics University Regensburg for Stargardt disease 1 and uncertain significance by Reproductive Health Research and Development BGI Genomics). The variant was identified in control databases in 113 of 282758 chromosomes (1 homozygous) at a frequency of 0.0003996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 93 of 10358 chromosomes (freq: 0.008979), European (non-Finnish) in 18 of 129090 chromosomes (freq: 0.000139) and South Asian in 2 of 30614 chromosomes (freq: 0.000065), but was not observed in the African, Latino, East Asian, European (Finnish), or Other populations. The p.Thr1253 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2021	This variant is associated with the following publications: (PMID: 25082829, 11726554, 26593885, 22661473, 23755871, 11385708, 19217903, 22076985, 28118664, 29925512, 31589614) -

Retinal dystrophy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 09, 2019	- -

ABCA4-related disorder

Uncertain:1Benign: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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 30, 2021	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). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 12, 2023

Variant summary: ABCA4 c.3758C>T (p.Thr1253Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251346 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00043 vs 0.0014), allowing no conclusion about variant significance. c.3758C>T has been reported in the literature as a non-informative genotype in cis with a different variant in the ABCA4 gene in cohorts with multifactorial age-related macular degeneration (AMD); bulls-eye maculopathy; inherited retinal disease and/or Stargardt disease (example, Shroyer_2001, Michaelides_2007, Zampaglione_2020, Sciezynska_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa or ABCA4-related opthalmological disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18024811, 26593885, 11726554, 32037395). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Severe early-childhood-onset retinal dystrophy

Uncertain:1

Uncertain significance, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NM_000350.2:c.3758C>T in the ABCA4 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported previously in individuals with fundus flavimaculatus or retinal disorders (PMID: 11385708, 23755871). Riveiro-Alvarez reported a patient with autosomal recessive Retinal Dystrophies habors c.[3758C>T; 5582G>A];[3943C>T] (PMID: 23755871). In addition, Cella et al. reported T1253M compound heterozygous with G1961E in a bull's eye maculopathy patient (PMID: 19217903). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PM3; PP3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.59

T;T

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.012

T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

2.0

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.0

.;N

REVEL

Pathogenic

0.65

Sift

Uncertain

0.022

.;D

Sift4G

Uncertain

0.049

D;T

Polyphen

1.0

.;D

Vest4

0.34

MVP

0.95

MPC

0.47

ClinPred

0.92

GERP RS

5.5

Varity_R

0.22

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over