chr1-94021406-A-T

Position:

• chr1-94021406-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000350.3(ABCA4):​c.4852T>A​(p.Trp1618Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. W1618C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.29

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a strand (size 7) in uniprot entity ABCA4_HUMAN there are 13 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 chr1-94021404-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 1-94021406-A-T is Pathogenic according to our data. Variant chr1-94021406-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190984.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-94021406-A-T is described in Lovd as [Likely_pathogenic]. Variant chr1-94021406-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.4852T>A	p.Trp1618Arg	missense_variant	35/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.4630T>A	p.Trp1544Arg	missense_variant	34/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.4852T>A	p.Trp1618Arg	missense_variant	35/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000460514.1	n.346T>A		non_coding_transcript_exon_variant	6/7	5
ABCA4	ENST00000470771.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.0	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-13	.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		1.0
MutPred		0.82		.;Gain of methylation at W1618 (P = 0.0199);
MVP		0.99
MPC		0.62
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs786205446; hg19: chr1-94486962;