10-126017293-C-T

Position:

chr10-126017293-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001288973.2(ADAM12):c.2707G>A(p.Ala903Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,593,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ADAM12
NM_001288973.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.923

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053457856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADAM12	NM_001288973.2 linkuse as main transcript	c.2707G>A	p.Ala903Thr	missense_variant	23/23	ENST00000448723.2	NP_001275902.1
ADAM12	NM_003474.6 linkuse as main transcript	c.2716G>A	p.Ala906Thr	missense_variant	23/23		NP_003465.3
ADAM12	XM_017016706.2 linkuse as main transcript	c.1549G>A	p.Ala517Thr	missense_variant	13/13		XP_016872195.1
ADAM12	XM_024448210.1 linkuse as main transcript	c.1378G>A	p.Ala460Thr	missense_variant	12/12		XP_024303978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM12	ENST00000448723.2 linkuse as main transcript	c.2707G>A	p.Ala903Thr	missense_variant	23/23	5	NM_001288973.2	ENSP00000391268.2		Q5JRP2
ADAM12	ENST00000368679.8 linkuse as main transcript	c.2716G>A	p.Ala906Thr	missense_variant	23/23	1		ENSP00000357668.4		O43184-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000275

AC:

AN:

218282

Hom.:

AF XY:

0.0000428

AC XY:

AN XY:

116910

show subpopulations

Gnomad AFR exome

AF:

0.0000747

Gnomad AMR exome

AF:

0.0000322

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000748

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000207

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000153

AC:

AN:

1441612

Hom.:

Cov.:

AF XY:

0.0000182

AC XY:

AN XY:

714806

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000239

Gnomad4 ASJ exome

AF:

0.0000389

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000483

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.0000136

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151796

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74130

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The c.2716G>A (p.A906T) alteration is located in exon 23 (coding exon 23) of the ADAM12 gene. This alteration results from a G to A substitution at nucleotide position 2716, causing the alanine (A) at amino acid position 906 to be replaced by a threonine (T). 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

0.075

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.7

DANN

Benign

0.97

DEOGEN2

Benign

0.17

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.47

M_CAP

Benign

0.0049

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.30

REVEL

Benign

0.074

Sift

Benign

0.077

Sift4G

Benign

0.11

Polyphen

0.0030

Vest4

0.14

MutPred

0.18

Gain of phosphorylation at A906 (P = 0.0502);

MVP

0.25

MPC

0.24

ClinPred

0.077

GERP RS

0.39

Varity_R

0.037

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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