rs25754

Positions:

• chr5-33534955-G-A
• chr5-33534955-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030955.4(ADAMTS12):​c.4484C>T​(p.Thr1495Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 1,611,788 control chromosomes in the GnomAD database, including 160,294 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.48 (18717 hom., cov: 32)
  • Exomes 𝑓: 0.43 (141577 hom.)
• Consequence: ADAMTS12 NM_030955.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37

Genes affected

ADAMTS12 (HGNC:14605): (ADAM metallopeptidase with thrombospondin type 1 motif 12) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of the family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS-1) motif. Individual members of this family differ in the number of C-terminal TS-1 motifs, and some have unique C-terminal domains. The enzyme encoded by this gene contains eight TS-1 motifs. It may play roles in pulmonary cells during fetal development or in tumor processes through its proteolytic activity or as a molecule potentially involved in regulation of cell adhesion. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4885685E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS12	NM_030955.4	c.4484C>T	p.Thr1495Ile	missense_variant	23/24	ENST00000504830.6	NP_112217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS12	ENST00000504830.6	c.4484C>T	p.Thr1495Ile	missense_variant	23/24	1	NM_030955.4	ENSP00000422554.1
ADAMTS12	ENST00000352040.7	c.4229C>T	p.Thr1410Ile	missense_variant	21/22	1		ENSP00000344847.3

Frequencies

GnomAD3 genomes AF: 0.481 AC: 72992 AN: 151834 Hom.: 18684 Cov.: 32

Gnomad AFR AF: 0.606

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.469

GnomAD3 exomes AF: 0.490 AC: 122233 AN: 249350 Hom.: 32447 AF XY: 0.487 AC XY: 65650 AN XY: 134838

Gnomad AFR exome AF: 0.615

Gnomad AMR exome AF: 0.598

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.784

Gnomad SAS exome AF: 0.627

Gnomad FIN exome AF: 0.379

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.430 AC: 627049 AN: 1459836 Hom.: 141577 Cov.: 40 AF XY: 0.432 AC XY: 314082 AN XY: 726242

Gnomad4 AFR exome AF: 0.619

Gnomad4 AMR exome AF: 0.587

Gnomad4 ASJ exome AF: 0.311

Gnomad4 EAS exome AF: 0.755

Gnomad4 SAS exome AF: 0.617

Gnomad4 FIN exome AF: 0.382

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.445

GnomAD4 genome AF: 0.481 AC: 73076 AN: 151952 Hom.: 18717 Cov.: 32 AF XY: 0.487 AC XY: 36155 AN XY: 74276

Gnomad4 AFR AF: 0.606

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.776

Gnomad4 SAS AF: 0.645

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.391

Gnomad4 OTH AF: 0.467

Alfa AF: 0.413 Hom.: 31910

Bravo AF: 0.497

TwinsUK AF: 0.389 AC: 1443

ALSPAC AF: 0.394 AC: 1517

ESP6500AA AF: 0.607 AC: 2673

ESP6500EA AF: 0.387 AC: 3326

ExAC AF: 0.489 AC: 59417

Asia WGS AF: 0.684 AC: 2378 AN: 3478

EpiCase AF: 0.385

EpiControl AF: 0.385

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-0.081
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0000025	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.78	N;N
REVEL	Benign	0.068
Sift	Benign	0.20	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.043	B;B
Vest4		0.19
MPC		0.43
ClinPred		0.010	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.33

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: rs25754; hg19: chr5-33535060; COSMIC: COSV61263782;