12-55726738-T-G

Position:

chr12-55726738-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_001780.6(CD63):c.388A>C(p.Asn130His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CD63
NM_001780.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60

Variant links:

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]

CD63 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity CD63_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD63	NM_001780.6 linkuse as main transcript	c.388A>C	p.Asn130His	missense_variant	5/8	ENST00000257857.9	NP_001771.1	P08962-1A0A024RB05

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CD63	ENST00000257857.9 linkuse as main transcript	c.388A>C	p.Asn130His	missense_variant	5/8	1	NM_001780.6	ENSP00000257857.4	P08962-1
CD63	ENST00000552067.5 linkuse as main transcript	c.109A>C	p.Asn37His	missense_variant	3/6	5		ENSP00000449684.1	F8VV56
CD63	ENST00000550050.5 linkuse as main transcript	n.*54A>C		non_coding_transcript_exon_variant	5/8	5		ENSP00000449435.1	F8VX62
CD63	ENST00000550050.5 linkuse as main transcript	n.*54A>C		3_prime_UTR_variant	5/8	5		ENSP00000449435.1	F8VX62

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251494

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.0000171

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2023

The c.388A>C (p.N130H) alteration is located in exon 5 (coding exon 4) of the CD63 gene. This alteration results from a A to C substitution at nucleotide position 388, causing the asparagine (N) at amino acid position 130 to be replaced by a histidine (H). 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

Benign

0.15

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;D;T;T;.;D;D;D;.;.;.;.;T

Eigen

Benign

0.10

Eigen_PC

Benign

0.072

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.75

.;T;.;T;.;.;.;.;T;T;T;T;T

M_CAP

Uncertain

0.096

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.6

.;M;.;.;.;M;M;M;.;.;.;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.2

N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.39

Sift

Uncertain

0.017

D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Benign

0.063

T;T;T;T;T;T;T;T;T;T;.;T;D

Polyphen

0.29

.;B;.;.;.;B;B;B;.;.;.;.;.

Vest4

0.35

MutPred

0.51

.;Gain of catalytic residue at N130 (P = 0.0093);.;.;.;Gain of catalytic residue at N130 (P = 0.0093);Gain of catalytic residue at N130 (P = 0.0093);Gain of catalytic residue at N130 (P = 0.0093);.;.;Gain of catalytic residue at N130 (P = 0.0093);Gain of catalytic residue at N130 (P = 0.0093);Gain of catalytic residue at N130 (P = 0.0093);

MVP

0.95

MPC

0.69

ClinPred

0.60

GERP RS

3.9

Varity_R

0.11

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over