NM_030955.4:c.4409A>C

Variant names:

• chr5-33546096-T-G
• rs777936614
• NM_030955.4:c.4409A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030955.4(ADAMTS12):​c.4409A>C​(p.His1470Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADAMTS12 NM_030955.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4409A>C	p.His1470Pro	missense	Exon 22 of 24	NP_112217.2	P58397-1
	ADAMTS12	NM_001324512.2		c.4154A>C	p.His1385Pro	missense	Exon 20 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.4409A>C	p.His1470Pro	missense	Exon 22 of 24	ENSP00000422554.1	P58397-1
	ADAMTS12	ENST00000352040.7	TSL:1	c.4154A>C	p.His1385Pro	missense	Exon 20 of 22	ENSP00000344847.3	P58397-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.065
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.085	N
PhyloP100		1.4
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.21
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.011	D
Polyphen		0.30	B
Vest4		0.60
MutPred		0.49		Loss of catalytic residue at H1470 (P = 0.0209)
MVP		0.75
MPC		0.51
ClinPred		0.71	D
GERP RS		4.2
Varity_R		0.57
gMVP		0.52
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs777936614; hg19: chr5-33546201;