12-55727279-T-C

Variant names:

• chr12-55727279-T-C
• rs1877513769
• NM_001780.6:c.127A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001780.6(CD63):​c.127A>G​(p.Ile43Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CD63 NM_001780.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0900
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08150789).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001780.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD63	NM_001780.6	MANE Select	c.127A>G	p.Ile43Val	missense	Exon 3 of 8	NP_001771.1	P08962-1
	CD63	NM_001257389.2		c.127A>G	p.Ile43Val	missense	Exon 3 of 8	NP_001244318.1	P08962-1
	CD63	NM_001257390.2		c.127A>G	p.Ile43Val	missense	Exon 3 of 8	NP_001244319.1	P08962-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD63	ENST00000257857.9	TSL:1 MANE Select	c.127A>G	p.Ile43Val	missense	Exon 3 of 8	ENSP00000257857.4	P08962-1
	CD63	ENST00000552692.5	TSL:1	c.127A>G	p.Ile43Val	missense	Exon 2 of 7	ENSP00000449337.1	P08962-1
	CD63	ENST00000552754.5	TSL:1	c.67-9A>G		intron	N/A	ENSP00000446807.1	P08962-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727092

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.72
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.89	L
PhyloP100		-0.090
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.17
Sift	Benign	0.72	T
Sift4G	Benign	0.92	T
Polyphen		0.0010	B
Vest4		0.070
MutPred		0.43		Gain of catalytic residue at A47 (P = 0.0055)
MVP		0.42
MPC		0.35
ClinPred		0.026	T
GERP RS		-2.7
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.13
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1877513769; hg19: chr12-56121063;