10-126036213-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001288973.2(ADAM12):c.2462G>A(p.Arg821Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,549,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: ADAM12 NM_001288973.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.389

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019089818).
• BP6: Variant 10-126036213-C-T is Benign according to our data. Variant chr10-126036213-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2398365.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM12	NM_001288973.2	c.2462G>A	p.Arg821Gln	missense_variant	21/23	ENST00000448723.2
ADAM12	NM_003474.6	c.2471G>A	p.Arg824Gln	missense_variant	21/23
ADAM12	XM_017016706.2	c.1304G>A	p.Arg435Gln	missense_variant	11/13
ADAM12	XM_024448210.1	c.1133G>A	p.Arg378Gln	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM12	ENST00000448723.2	c.2462G>A	p.Arg821Gln	missense_variant	21/23	5	NM_001288973.2	A2
ADAM12	ENST00000368679.8	c.2471G>A	p.Arg824Gln	missense_variant	21/23	1		P2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000352 AC: 7 AN: 198876 Hom.: 0 AF XY: 0.0000367 AC XY: 4 AN XY: 109068

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000825

Gnomad SAS exome AF: 0.0000424

Gnomad FIN exome AF: 0.000146

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.0000336 AC: 47 AN: 1397526 Hom.: 0 Cov.: 31 AF XY: 0.0000390 AC XY: 27 AN XY: 692748

Gnomad4 AFR exome AF: 0.0000343

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000581

Gnomad4 SAS exome AF: 0.0000130

Gnomad4 FIN exome AF: 0.000152

Gnomad4 NFE exome AF: 0.0000295

Gnomad4 OTH exome AF: 0.0000347

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74412

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000456 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	8.8
Dann	Benign	0.25
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.036
Sift	Benign	1.0	T
Sift4G	Benign	0.98	T
Polyphen		0.0010	B
Vest4		0.097
MVP		0.23
MPC		0.26
ClinPred		0.027	T
GERP RS		0.91
Varity_R		0.022
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs372825649; hg19: chr10-127724782;