1-94011334-G-T

Position:

chr1-94011334-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000350.3(ABCA4):c.5512C>A(p.His1838Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1838D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ABCA4
NM_000350.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.96

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a helix (size 23) in uniprot entity ABCA4_HUMAN there are 30 pathogenic changes around while only 1 benign (97%) in NM_000350.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-94011334-G-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.943

PP5

Variant 1-94011334-G-T is Pathogenic according to our data. Variant chr1-94011334-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-94011334-G-T is described in Lovd as [Pathogenic]. Variant chr1-94011334-G-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94011334-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3 linkuse as main transcript	c.5512C>A	p.His1838Asn	missense_variant	39/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1 linkuse as main transcript	c.5290C>A	p.His1764Asn	missense_variant	38/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4 linkuse as main transcript	c.5512C>A	p.His1838Asn	missense_variant	39/50	1	NM_000350.3	ENSP00000359245	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251382

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 20, 2023

This variant disrupts the p.His1838 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28771251; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 33375396). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 236133). This missense change has been observed in individual(s) with ABCA4 associated conditions (PMID: 15192030; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1838 of the ABCA4 protein (p.His1838Asn). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Uncertain

0.65

D;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.054

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.033

MutationAssessor

Uncertain

2.1

.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.7

.;D

REVEL

Pathogenic

0.71

Sift

Benign

0.24

.;T

Sift4G

Benign

0.43

T;T

Polyphen

1.0

.;D

Vest4

0.94

MutPred

0.86

.;Gain of MoRF binding (P = 0.1052);

MVP

0.90

MPC

0.49

ClinPred

0.94

GERP RS

4.7

Varity_R

0.75

gMVP

0.91

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