NM_030955.4:c.4409A>C

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

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37
Variant links:
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]

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ACMG classification

Classification made for transcript

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 rank MANE Protein UniProt
ADAMTS12NM_030955.4 linkc.4409A>C p.His1470Pro missense_variant Exon 22 of 24 ENST00000504830.6 NP_112217.2 P58397-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADAMTS12ENST00000504830.6 linkc.4409A>C p.His1470Pro missense_variant Exon 22 of 24 1 NM_030955.4 ENSP00000422554.1 P58397-1
ADAMTS12ENST00000352040.7 linkc.4154A>C p.His1385Pro missense_variant Exon 20 of 22 1 ENSP00000344847.3 P58397-3

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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 10, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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;.
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; API