rs25754

Variant names:

• chr5-33534955-G-A
• rs25754
• NM_030955.4:c.4484C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 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: 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
• Publications: 29 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030955.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS12	NM_030955.4	MANE Select	c.4484C>T	p.Thr1495Ile	missense	Exon 23 of 24	NP_112217.2	P58397-1
	ADAMTS12	NM_001324512.2		c.4229C>T	p.Thr1410Ile	missense	Exon 21 of 22	NP_001311441.1	P58397-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS12	ENST00000504830.6	TSL:1 MANE Select	c.4484C>T	p.Thr1495Ile	missense	Exon 23 of 24	ENSP00000422554.1	P58397-1
	ADAMTS12	ENST00000352040.7	TSL:1	c.4229C>T	p.Thr1410Ile	missense	Exon 21 of 22	ENSP00000344847.3	P58397-3

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

GnomAD2 exomes AF: 0.490 AC: 122233 AN: 249350 AF XY: 0.487

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 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

African (AFR) AF: 0.619 AC: 20677 AN: 33402

American (AMR) AF: 0.587 AC: 25946 AN: 44200

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 8087 AN: 26020

East Asian (EAS) AF: 0.755 AC: 29914 AN: 39644

South Asian (SAS) AF: 0.617 AC: 52981 AN: 85916

European-Finnish (FIN) AF: 0.382 AC: 20360 AN: 53300

Middle Eastern (MID) AF: 0.457 AC: 2618 AN: 5728

European-Non Finnish (NFE) AF: 0.396 AC: 439639 AN: 1111324

Other (OTH) AF: 0.445 AC: 26827 AN: 60302

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

African (AFR) AF: 0.606 AC: 25109 AN: 41402

American (AMR) AF: 0.497 AC: 7597 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1108 AN: 3470

East Asian (EAS) AF: 0.776 AC: 4002 AN: 5160

South Asian (SAS) AF: 0.645 AC: 3108 AN: 4822

European-Finnish (FIN) AF: 0.385 AC: 4061 AN: 10552

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.391 AC: 26571 AN: 67954

Other (OTH) AF: 0.467 AC: 986 AN: 2110

Alfa AF: 0.428 Hom.: 47653

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 v4.9

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
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.068
Sift	Benign	0.20	T
Sift4G	Benign	0.29	T
Polyphen		0.043	B
Vest4		0.19
MPC		0.43
ClinPred		0.010	T
GERP RS		4.1
Varity_R		0.12
gMVP		0.33
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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