rs483352912

Positions:

• chr15-58679193-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001110.4(ADAM10):​c.415C>T​(p.Pro139Ser) variant causes a missense change involving the alteration of a 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 no classification for the single variant (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM10 NM_001110.4 missense
• Clinical Significance: no classification for the single variant no classification for the single variant P:1
• Conservation: PhyloP100: 9.56

Genes affected

ADAM10 (HGNC:188): (ADAM metallopeptidase domain 10) Members of the ADAM family are cell surface proteins with a unique structure possessing both potential adhesion and protease domains. This gene encodes and ADAM family member that cleaves many proteins including TNF-alpha and E-cadherin. Alternate splicing results in multiple transcript variants encoding different proteins that may undergo similar processing. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADAM10. . Gene score misZ 3.3058 (greater than the threshold 3.09). Trascript score misZ 3.9118 (greater than threshold 3.09). GenCC has associacion of gene with reticulate acropigmentation of Kitamura.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM10	NM_001110.4	c.415C>T	p.Pro139Ser	missense_variant	4/16	ENST00000260408.8	NP_001101.1
ADAM10	NM_001320570.2	c.415C>T	p.Pro139Ser	missense_variant	4/15		NP_001307499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM10	ENST00000260408.8	c.415C>T	p.Pro139Ser	missense_variant	4/16	1	NM_001110.4	ENSP00000260408	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: no classification for the single variant

Submissions summary: Pathogenic:1

Revision: no classification for the single variant

Submissions by phenotype

Reticulate acropigmentation of Kitamura Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.64
Sift	Benign	0.074	T
Sift4G	Benign	0.12	T
Polyphen		0.93	P
Vest4		0.91
MutPred		0.74		Loss of phosphorylation at T134 (P = 0.155);
MVP		0.75
MPC		0.52
ClinPred		0.94	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.85

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: rs483352912; hg19: chr15-58971392;