15-58610440-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001110.4(ADAM10):c.1882C>T(p.Pro628Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADAM10 NM_001110.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ADAM10
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM10	NM_001110.4	c.1882C>T	p.Pro628Ser	missense_variant	14/16	ENST00000260408.8
ADAM10	NM_001320570.2	c.1789C>T	p.Pro597Ser	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM10	ENST00000260408.8	c.1882C>T	p.Pro628Ser	missense_variant	14/16	1	NM_001110.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727240

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 20, 2023

The c.1882C>T (p.P628S) alteration is located in exon 14 (coding exon 14) of the ADAM10 gene. This alteration results from a C to T substitution at nucleotide position 1882, causing the proline (P) at amino acid position 628 to be replaced by a serine (S). 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	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.020	D
Polyphen		0.99	D
Vest4		0.65
MutPred		0.78		Gain of glycosylation at P628 (P = 0.0986);
MVP		0.67
MPC		1.4
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.64
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-58902639;