chr5-33576092-G-T

Position:

• chr5-33576092-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030955.4(ADAMTS12):​c.3934C>A​(p.His1312Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAMTS12 NM_030955.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13934168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS12	NM_030955.4	c.3934C>A	p.His1312Asn	missense_variant	19/24	ENST00000504830.6	NP_112217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS12	ENST00000504830.6	c.3934C>A	p.His1312Asn	missense_variant	19/24	1	NM_030955.4	ENSP00000422554	P1
ADAMTS12	ENST00000352040.7	c.3679C>A	p.His1227Asn	missense_variant	17/22	1		ENSP00000344847

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Nov 06, 2023

The c.3934C>A (p.H1312N) alteration is located in exon 19 (coding exon 19) of the ADAMTS12 gene. This alteration results from a C to A substitution at nucleotide position 3934, causing the histidine (H) at amino acid position 1312 to be replaced by an asparagine (N). 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	0.063
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.8
DANN	Benign	0.41
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.082
Sift	Benign	0.57	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.20	B;B
Vest4		0.29
MutPred		0.44		Gain of loop (P = 0.1069);.;
MVP		0.54
MPC		0.17
ClinPred		0.21	T
GERP RS		4.7
Varity_R		0.14
gMVP		0.19

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: rs1746694284; hg19: chr5-33576197;