10-126046075-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001288973.2(ADAM12):c.1975A>G(p.Met659Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,178 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (10 hom.)
• Consequence: ADAM12 NM_001288973.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.471

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034144223).
• BP6: Variant 10-126046075-T-C is Benign according to our data. Variant chr10-126046075-T-C is described in ClinVar as [Benign]. Clinvar id is 709836.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00697 (1061/152304) while in subpopulation AFR AF= 0.0243 (1008/41554). AF 95% confidence interval is 0.023. There are 9 homozygotes in gnomad4. There are 484 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM12	NM_001288973.2	c.1975A>G	p.Met659Val	missense_variant	17/23	ENST00000448723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM12	ENST00000448723.2	c.1975A>G	p.Met659Val	missense_variant	17/23	5	NM_001288973.2	A2
ADAM12	ENST00000368679.8	c.1984A>G	p.Met662Val	missense_variant	17/23	1		P2
ADAM12	ENST00000368676.8	c.1984A>G	p.Met662Val	missense_variant	17/19	1		A2

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 1060 AN: 152186 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00170 AC: 428 AN: 251484 Hom.: 6 AF XY: 0.00119 AC XY: 162 AN XY: 135916

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.000781 AC: 1142 AN: 1461874 Hom.: 10 Cov.: 31 AF XY: 0.000663 AC XY: 482 AN XY: 727242

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00697 AC: 1061 AN: 152304 Hom.: 9 Cov.: 32 AF XY: 0.00650 AC XY: 484 AN XY: 74480

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00199 Hom.: 7

Bravo AF: 0.00843

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.057
Dann	Benign	0.33
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.052	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	-0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.039
Sift	Benign	0.30	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0	B;B
Vest4		0.14
MVP		0.39
MPC		0.23
ClinPred		0.0094	T
GERP RS		-5.2
Varity_R		0.045
gMVP		0.16

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: rs115100580; hg19: chr10-127734644;