chr5-33546096-T-G

Position:

• chr5-33546096-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 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. 14/21 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS12	NM_030955.4	c.4409A>C	p.His1470Pro	missense_variant	22/24	ENST00000504830.6	NP_112217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS12	ENST00000504830.6	c.4409A>C	p.His1470Pro	missense_variant	22/24	1	NM_030955.4	ENSP00000422554	P1
ADAMTS12	ENST00000352040.7	c.4154A>C	p.His1385Pro	missense_variant	20/22	1		ENSP00000344847

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.4409A>C (p.H1470P) alteration is located in exon 22 (coding exon 22) of the ADAMTS12 gene. This alteration results from a A to C substitution at nucleotide position 4409, causing the histidine (H) at amino acid position 1470 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.085	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.30	B;P
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

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-33546201;