rs62646862

Positions:

• chr1-94103130-C-A
• chr1-94103130-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM5

The NM_000350.3(ABCA4):​c.455G>T​(p.Arg152Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R152Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ABCA4 NM_000350.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000350.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-94103130-C-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.455G>T	p.Arg152Leu	missense_variant	5/50	ENST00000370225.4	NP_000341.2
ABCA4	XM_047416704.1	c.455G>T	p.Arg152Leu	missense_variant	5/49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA4	ENST00000370225.4	c.455G>T	p.Arg152Leu	missense_variant	5/50	1	NM_000350.3	ENSP00000359245.3
ABCA4	ENST00000649773.1	c.455G>T	p.Arg152Leu	missense_variant	5/19			ENSP00000496882.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251232 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135794

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461694 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727168

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: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.2	M;.
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.64
Sift	Benign	0.052	T;.
Sift4G	Benign	0.15	T;.
Polyphen		0.0070	B;.
Vest4		0.50
MutPred		0.64		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		0.85
MPC		0.12
ClinPred		0.85	D
GERP RS		2.6
Varity_R		0.13
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs62646862; hg19: chr1-94568686;