1-94021695-G-C

Position:

• chr1-94021695-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PM1 PM2 PM5 PP5_Moderate BP4

The NM_000350.3(ABCA4):​c.4793C>G​(p.Ala1598Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1598D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.865

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a helix (size 6) in uniprot entity ABCA4_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr1-94021695-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 99321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 1-94021695-G-C is Pathogenic according to our data. Variant chr1-94021695-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1057512.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-94021695-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.22534063). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA4	NM_000350.3	c.4793C>G	p.Ala1598Gly	missense_variant	34/50	ENST00000370225.4
ABCA4	XM_047416704.1	c.4571C>G	p.Ala1524Gly	missense_variant	33/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA4	ENST00000370225.4	c.4793C>G	p.Ala1598Gly	missense_variant	34/50	1	NM_000350.3	P1
ABCA4	ENST00000460514.1	n.287C>G		non_coding_transcript_exon_variant	5/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2023

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1598 of the ABCA4 protein (p.Ala1598Gly). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala1598 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10958761, 19074458, 23105016, 28559085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 1057512). This missense change has been observed in individual(s) with inherited retinal dystrophy and/or Stargardt disease (PMID: 26161775; Invitae). This variant is not present in population databases (gnomAD no frequency). -

Retinitis pigmentosa 19 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Dr.Nikuei Genetic Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.2	.;M
MutationTaster	Benign	0.88	D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	.;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.018	.;D
Sift4G	Benign	0.33	T;T
Polyphen		0.49	.;P
Vest4		0.32
MutPred		0.45		.;Loss of stability (P = 0.0661);
MVP		0.92
MPC		0.23
ClinPred		0.51	D
GERP RS		4.7
Varity_R		0.20
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-94487251;