10-126036180-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001288973.2(ADAM12):c.2495C>T(p.Pro832Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000735 in 1,360,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ADAM12 NM_001288973.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27752656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM12	NM_001288973.2	c.2495C>T	p.Pro832Leu	missense_variant	21/23	ENST00000448723.2
ADAM12	NM_003474.6	c.2504C>T	p.Pro835Leu	missense_variant	21/23
ADAM12	XM_017016706.2	c.1337C>T	p.Pro446Leu	missense_variant	11/13
ADAM12	XM_024448210.1	c.1166C>T	p.Pro389Leu	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM12	ENST00000448723.2	c.2495C>T	p.Pro832Leu	missense_variant	21/23	5	NM_001288973.2	A2
ADAM12	ENST00000368679.8	c.2504C>T	p.Pro835Leu	missense_variant	21/23	1		P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360122 Hom.: 0 Cov.: 30 AF XY: 0.00000149 AC XY: 1 AN XY: 671372

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: 0.0000141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Oct 05, 2021

The c.2504C>T (p.P835L) alteration is located in exon 21 (coding exon 21) of the ADAM12 gene. This alteration results from a C to T substitution at nucleotide position 2504, causing the proline (P) at amino acid position 835 to be replaced by a leucine (L). 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	-0.20	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.11
Sift	Benign	0.057	T
Sift4G	Benign	0.12	T
Polyphen		0.0090	B
Vest4		0.27
MutPred		0.24		Loss of glycosylation at P835 (P = 0.0273);
MVP		0.45
MPC		0.24
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.21
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs201897440; hg19: chr10-127724749;