10-126038324-G-T

Variant names:

• chr10-126038324-G-T
• rs369863403
• NM_001288973.2:c.2266C>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.2266C>A​(p.Arg756Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,376 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R756H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ADAM12 NM_001288973.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.650
• 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=0.03744358).

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.2266C>A	p.Arg756Ser	missense	Exon 20 of 23	NP_001275902.1	Q5JRP2
	ADAM12	NM_003474.6		c.2275C>A	p.Arg759Ser	missense	Exon 20 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.2266C>A	p.Arg756Ser	missense	Exon 20 of 23	ENSP00000391268.2	Q5JRP2
	ADAM12	ENST00000368679.8	TSL:1	c.2275C>A	p.Arg759Ser	missense	Exon 20 of 23	ENSP00000357668.4	O43184-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453376 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721876

African (AFR) AF: 0.00 AC: 0 AN: 33268

American (AMR) AF: 0.00 AC: 0 AN: 44024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25694

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.00 AC: 0 AN: 85116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107064

Other (OTH) AF: 0.00 AC: 0 AN: 59934

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0080
DANN	Benign	0.29
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.44	N
PhyloP100		-0.65
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.82	N
REVEL	Benign	0.0030
Sift	Benign	0.81	T
Sift4G	Benign	0.96	T
Polyphen		0.0030	B
Vest4		0.060
MutPred		0.31		Gain of glycosylation at R759 (P = 0.0043)
MVP		0.12
MPC		0.26
ClinPred		0.026	T
GERP RS		-4.4
Varity_R		0.075
gMVP		0.25
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs369863403; hg19: chr10-127726893; COSMIC: COSV100900208; COSMIC: COSV100900208;