10-126330456-C-G

Variant names:

• chr10-126330456-C-G
• rs3740199
• NM_001288973.2:c.142G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001288973.2(ADAM12):​c.142G>C​(p.Gly48Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,612,416 control chromosomes in the GnomAD database, including 247,353 homozygotes. 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 0.57 (24811 hom., cov: 32)
  • Exomes 𝑓: 0.55 (222542 hom.)
• Consequence: ADAM12 NM_001288973.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.87
• Publications: 59 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.530847E-6).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

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.142G>C	p.Gly48Arg	missense	Exon 2 of 23	NP_001275902.1	Q5JRP2
	ADAM12	NM_003474.6		c.142G>C	p.Gly48Arg	missense	Exon 2 of 23	NP_003465.3
	ADAM12	NM_021641.5		c.142G>C	p.Gly48Arg	missense	Exon 2 of 19	NP_067673.2	O43184-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM12	ENST00000448723.2	TSL:5 MANE Select	c.142G>C	p.Gly48Arg	missense	Exon 2 of 23	ENSP00000391268.2	Q5JRP2
	ADAM12	ENST00000368679.8	TSL:1	c.142G>C	p.Gly48Arg	missense	Exon 2 of 23	ENSP00000357668.4	O43184-1
	ADAM12	ENST00000368676.8	TSL:1	c.142G>C	p.Gly48Arg	missense	Exon 2 of 19	ENSP00000357665.4	O43184-2

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86600 AN: 151892 Hom.: 24803 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.483

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.491

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.575

GnomAD2 exomes AF: 0.556 AC: 139328 AN: 250642 AF XY: 0.550

Gnomad AFR exome AF: 0.588

Gnomad AMR exome AF: 0.594

Gnomad ASJ exome AF: 0.684

Gnomad EAS exome AF: 0.491

Gnomad FIN exome AF: 0.626

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.575

GnomAD4 exome AF: 0.549 AC: 802280 AN: 1460406 Hom.: 222542 Cov.: 48 AF XY: 0.546 AC XY: 396732 AN XY: 726472

African (AFR) AF: 0.587 AC: 19605 AN: 33410

American (AMR) AF: 0.593 AC: 26361 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 17843 AN: 26086

East Asian (EAS) AF: 0.495 AC: 19619 AN: 39632

South Asian (SAS) AF: 0.411 AC: 35350 AN: 85990

European-Finnish (FIN) AF: 0.623 AC: 33266 AN: 53372

Middle Eastern (MID) AF: 0.572 AC: 3295 AN: 5764

European-Non Finnish (NFE) AF: 0.552 AC: 613670 AN: 1111360

Other (OTH) AF: 0.551 AC: 33271 AN: 60340

GnomAD4 genome AF: 0.570 AC: 86651 AN: 152010 Hom.: 24811 Cov.: 32 AF XY: 0.568 AC XY: 42215 AN XY: 74272

African (AFR) AF: 0.583 AC: 24168 AN: 41452

American (AMR) AF: 0.605 AC: 9237 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2328 AN: 3470

East Asian (EAS) AF: 0.492 AC: 2540 AN: 5164

South Asian (SAS) AF: 0.416 AC: 2001 AN: 4814

European-Finnish (FIN) AF: 0.618 AC: 6515 AN: 10550

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.560 AC: 38034 AN: 67976

Other (OTH) AF: 0.571 AC: 1205 AN: 2110

Alfa AF: 0.296 Hom.: 2877

Bravo AF: 0.575

TwinsUK AF: 0.530 AC: 1965

ALSPAC AF: 0.543 AC: 2093

ESP6500AA AF: 0.588 AC: 2589

ESP6500EA AF: 0.564 AC: 4850

ExAC AF: 0.550 AC: 66819

EpiCase AF: 0.567

EpiControl AF: 0.571

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.0060
DANN	Benign	0.21
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0000095	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.55	N
PhyloP100		-1.9
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.020
Sift	Benign	0.76	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.25		Gain of MoRF binding (P = 0.0578)
MPC		0.27
ClinPred		0.0018	T
GERP RS		-3.9
Varity_R		0.033
gMVP		0.72
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3740199; hg19: chr10-128019025; COSMIC: COSV64105708;