15-58611090-G-C

Position:

• chr15-58611090-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001110.4(ADAM10):​c.1713C>G​(p.Ile571Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAM10 NM_001110.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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]

ADAM10 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM10	NM_001110.4	c.1713C>G	p.Ile571Met	missense_variant	13/16	ENST00000260408.8	NP_001101.1
ADAM10	NM_001320570.2	c.1620C>G	p.Ile540Met	missense_variant	12/15		NP_001307499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM10	ENST00000260408.8	c.1713C>G	p.Ile571Met	missense_variant	13/16	1	NM_001110.4	ENSP00000260408.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.1713C>G (p.I571M) alteration is located in exon 13 (coding exon 13) of the ADAM10 gene. This alteration results from a C to G substitution at nucleotide position 1713, causing the isoleucine (I) at amino acid position 571 to be replaced by a methionine (M). 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	0.45
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.0	M
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.24
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.87	P
Vest4		0.64
MutPred		0.52		Gain of disorder (P = 0.0376);
MVP		0.63
MPC		1.8
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-58903289;