Genetic Variant NM_001288973.2:c.2482G>A (chr10-126036193-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001288973.2(ADAM12):c.2482G>A(p.Val828Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,384,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ADAM12
NM_001288973.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

ADAM12 (HGNC:190): (ADAM metallopeptidase domain 12) This gene encodes a member of a family of proteins that are structurally related to snake venom disintegrins and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. Expression of this gene has been used as a maternal serum marker for pre-natal development. Alternative splicing results in multiple transcript variants encoding different isoforms. Shorter isoforms are secreted, while longer isoforms are membrane-bound form. [provided by RefSeq, Jan 2014]

ADAM12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16987297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ADAM12	NM_001288973.2 link	c.2482G>A	p.Val828Ile	missense_variant	Exon 21 of 23	ENST00000448723.2	NP_001275902.1
ADAM12	NM_003474.6 link	c.2491G>A	p.Val831Ile	missense_variant	Exon 21 of 23		NP_003465.3
ADAM12	XM_017016706.2 link	c.1324G>A	p.Val442Ile	missense_variant	Exon 11 of 13		XP_016872195.1
ADAM12	XM_024448210.1 link	c.1153G>A	p.Val385Ile	missense_variant	Exon 10 of 12		XP_024303978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM12	ENST00000448723.2 link	c.2482G>A	p.Val828Ile	missense_variant	Exon 21 of 23	5	NM_001288973.2	ENSP00000391268.2		Q5JRP2
ADAM12	ENST00000368679.8 link	c.2491G>A	p.Val831Ile	missense_variant	Exon 21 of 23	1		ENSP00000357668.4		O43184-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000317

AC:

AN:

189392

Hom.:

AF XY:

0.0000192

AC XY:

AN XY:

103950

show subpopulations

Gnomad AFR exome

AF:

0.0000825

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000455

Gnomad FIN exome

AF:

0.0000501

Gnomad NFE exome

AF:

0.0000218

Gnomad OTH exome

AF:

0.000239

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1384290

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

685238

show subpopulations

Gnomad4 AFR exome

AF:

0.000105

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000296

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.0000148

Gnomad4 OTH exome

AF:

0.0000526

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000388

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2491G>A (p.V831I) alteration is located in exon 21 (coding exon 21) of the ADAM12 gene. This alteration results from a G to A substitution at nucleotide position 2491, causing the valine (V) at amino acid position 831 to be replaced by an isoleucine (I). 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

0.073

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.29

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.60

M_CAP

Benign

0.012

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.33

REVEL

Benign

0.10

Sift

Benign

0.43

Sift4G

Benign

0.45

Polyphen

0.93

Vest4

0.092

MVP

0.39

MPC

0.19

ClinPred

0.054

GERP RS

3.3

Varity_R

0.030

gMVP

0.053

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