rs886044723

Positions:

• chr1-94080621-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000350.3(ABCA4):​c.956T>G​(p.Leu319Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.70

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]

LOC124904222 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a helix (size 10) in uniprot entity ABCA4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000350.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA4	NM_000350.3	c.956T>G	p.Leu319Arg	missense_variant	8/50	ENST00000370225.4	NP_000341.2
LOC124904222	XR_007066231.1	n.203-3108A>C		intron_variant, non_coding_transcript_variant
ABCA4	XM_047416704.1	c.956T>G	p.Leu319Arg	missense_variant	8/49		XP_047272660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.956T>G	p.Leu319Arg	missense_variant	8/50	1	NM_000350.3	ENSP00000359245	P1
ABCA4	ENST00000649773.1	c.956T>G	p.Leu319Arg	missense_variant	8/19			ENSP00000496882

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.092
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.092	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.022	D;.
Polyphen		0.98	D;.
Vest4		0.75
MutPred		0.76		Loss of methylation at K314 (P = 0.0559);Loss of methylation at K314 (P = 0.0559);
MVP		0.94
MPC		0.35
ClinPred		0.96	D
GERP RS		4.1
Varity_R		0.59
gMVP		0.92

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

Other links and lift over

dbSNP: rs886044723; hg19: chr1-94546177;