12-55726770-A-T

Variant names:

• chr12-55726770-A-T
• rs1047139929
• NM_001780.6:c.356T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001780.6(CD63):​c.356T>A​(p.Phe119Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000287 in 1,461,766 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F119L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CD63 NM_001780.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

Genes affected

CD63 (HGNC:1692): (CD63 molecule) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. The encoded protein is a cell surface glycoprotein that is known to complex with integrins. It may function as a blood platelet activation marker. Deficiency of this protein is associated with Hermansky-Pudlak syndrome. Also this gene has been associated with tumor progression. Alternative splicing results in multiple transcript variants encoding different protein isoforms. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD63	NM_001780.6	c.356T>A	p.Phe119Tyr	missense_variant	Exon 5 of 8	ENST00000257857.9	NP_001771.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD63	ENST00000257857.9	c.356T>A	p.Phe119Tyr	missense_variant	Exon 5 of 8	1	NM_001780.6	ENSP00000257857.4
CD63	ENST00000552067.5	c.77T>A	p.Phe26Tyr	missense_variant	Exon 3 of 6	5		ENSP00000449684.1
CD63	ENST00000550050.5	n.*22T>A		non_coding_transcript_exon_variant	Exon 5 of 8	5		ENSP00000449435.1
CD63	ENST00000550050.5	n.*22T>A		3_prime_UTR_variant	Exon 5 of 8	5		ENSP00000449435.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251482 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135918

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461766 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727188

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: 0.0000369

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000312 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.356T>A (p.F119Y) alteration is located in exon 5 (coding exon 4) of the CD63 gene. This alteration results from a T to A substitution at nucleotide position 356, causing the phenylalanine (F) at amino acid position 119 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;D;T;T;.;D;D;D;.;.;.;.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.64	.;T;.;T;.;.;.;.;T;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.9	.;L;.;.;.;L;L;L;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.085	T;T;T;T;T;T;T;T;T;T;T;T;D
Sift4G	Benign	0.11	T;T;T;T;T;T;T;T;T;T;.;T;T
Polyphen		0.42	.;B;.;.;.;B;B;B;.;.;.;.;.
Vest4		0.40
MutPred		0.70		.;Loss of stability (P = 0.0819);.;.;.;Loss of stability (P = 0.0819);Loss of stability (P = 0.0819);Loss of stability (P = 0.0819);.;.;Loss of stability (P = 0.0819);Loss of stability (P = 0.0819);Loss of stability (P = 0.0819);
MVP		0.77
MPC		1.3
ClinPred		0.84	D
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.21
gMVP		0.83

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: rs1047139929; hg19: chr12-56120554;