10-126039421-C-T

Variant names:

• chr10-126039421-C-T
• rs750102403
• NM_001288973.2:c.2113G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001288973.2(ADAM12):​c.2113G>A​(p.Gly705Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADAM12 NM_001288973.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048117787).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288973.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM12	NM_001288973.2	MANE Select	c.2113G>A	p.Gly705Ser	missense	Exon 19 of 23	NP_001275902.1	Q5JRP2
	ADAM12	NM_003474.6		c.2122G>A	p.Gly708Ser	missense	Exon 19 of 23	NP_003465.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM12	ENST00000448723.2	TSL:5 MANE Select	c.2113G>A	p.Gly705Ser	missense	Exon 19 of 23	ENSP00000391268.2	Q5JRP2
	ADAM12	ENST00000368679.8	TSL:1	c.2122G>A	p.Gly708Ser	missense	Exon 19 of 23	ENSP00000357668.4	O43184-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251450 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

African (AFR) AF: 0.0000724 AC: 3 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.77	N
PhyloP100		2.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.071
Sift	Benign	0.57	T
Sift4G	Benign	0.61	T
Polyphen		0.0020	B
Vest4		0.15
MVP		0.40
MPC		0.23
ClinPred		0.068	T
GERP RS		4.0
Varity_R		0.054
gMVP		0.32
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs750102403; hg19: chr10-127727990;