5-65188165-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_197941.4(ADAMTS6):​c.2761A>G​(p.Thr921Ala) 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. 13/21 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

ADAMTS6
NM_197941.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.56
Variant links:
Genes affected
ADAMTS6 (HGNC:222): (ADAM metallopeptidase with thrombospondin type 1 motif 6) 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) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The encoded preproprotein is proteolytically processed to generate the mature enzyme. Expression of this gene may be regulated by the cytokine TNF-alpha. [provided by RefSeq, Mar 2016]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.26979536).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADAMTS6NM_197941.4 linkc.2761A>G p.Thr921Ala missense_variant 22/25 ENST00000381055.8 NP_922932.2 Q9UKP5-1Q5IR90

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADAMTS6ENST00000381055.8 linkc.2761A>G p.Thr921Ala missense_variant 22/251 NM_197941.4 ENSP00000370443.3 Q9UKP5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 19, 2024The c.2761A>G (p.T921A) alteration is located in exon 22 (coding exon 21) of the ADAMTS6 gene. This alteration results from a A to G substitution at nucleotide position 2761, causing the threonine (T) at amino acid position 921 to be replaced by an alanine (A). 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
0.079
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.053
T
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.076
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.76
T
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.27
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Uncertain
2.7
M
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.16
Sift
Benign
0.083
T
Sift4G
Benign
0.25
T
Polyphen
0.0040
B
Vest4
0.32
MutPred
0.51
Gain of methylation at R920 (P = 0.0905);
MVP
0.27
MPC
0.53
ClinPred
0.59
D
GERP RS
2.9
Varity_R
0.091
gMVP
0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-64483992; API