chr10-126036211-C-A

Position:

• chr10-126036211-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001288973.2(ADAM12):​c.2464G>T​(p.Ala822Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAM12 NM_001288973.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.244

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

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=0.052568763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM12	NM_001288973.2	c.2464G>T	p.Ala822Ser	missense_variant	21/23	ENST00000448723.2	NP_001275902.1
ADAM12	NM_003474.6	c.2473G>T	p.Ala825Ser	missense_variant	21/23		NP_003465.3
ADAM12	XM_017016706.2	c.1306G>T	p.Ala436Ser	missense_variant	11/13		XP_016872195.1
ADAM12	XM_024448210.1	c.1135G>T	p.Ala379Ser	missense_variant	10/12		XP_024303978.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM12	ENST00000448723.2	c.2464G>T	p.Ala822Ser	missense_variant	21/23	5	NM_001288973.2	ENSP00000391268.2
ADAM12	ENST00000368679.8	c.2473G>T	p.Ala825Ser	missense_variant	21/23	1		ENSP00000357668.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395980 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 691944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.2473G>T (p.A825S) alteration is located in exon 21 (coding exon 21) of the ADAM12 gene. This alteration results from a G to T substitution at nucleotide position 2473, causing the alanine (A) at amino acid position 825 to be replaced by a serine (S). 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	0.074
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.050
Sift	Benign	0.46	T
Sift4G	Benign	0.67	T
Polyphen		0.10	B
Vest4		0.11
MutPred		0.13		Gain of phosphorylation at A825 (P = 0.0061);
MVP		0.20
MPC		0.21
ClinPred		0.090	T
GERP RS		0.77
Varity_R		0.029
gMVP		0.10

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-127724780;