chr5-5146285-G-T

Variant names:

• chr5-5146285-G-T
• rs766063759
• NM_139056.4:c.331G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_139056.4(ADAMTS16):​c.331G>T​(p.Asp111Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAMTS16 NM_139056.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.62

Genes affected

ADAMTS16 (HGNC:17108): (ADAM metallopeptidase with thrombospondin type 1 motif 16) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS family members 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 protein, which may inhibit chondrosarcoma cell proliferation and migration. This gene may regulate blood pressure. [provided by RefSeq, May 2016]

ENSG00000250866 (HGNC:58093):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS16	NM_139056.4	c.331G>T	p.Asp111Tyr	missense_variant	Exon 3 of 23	ENST00000274181.7	NP_620687.2
ADAMTS16	XM_047416874.1	c.331G>T	p.Asp111Tyr	missense_variant	Exon 3 of 22		XP_047272830.1
ADAMTS16	XM_047416875.1	c.331G>T	p.Asp111Tyr	missense_variant	Exon 3 of 20		XP_047272831.1
ADAMTS16	NR_136935.2	n.469G>T		non_coding_transcript_exon_variant	Exon 3 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS16	ENST00000274181.7	c.331G>T	p.Asp111Tyr	missense_variant	Exon 3 of 23	2	NM_139056.4	ENSP00000274181.7
ADAMTS16	ENST00000511368.5	c.331G>T	p.Asp111Tyr	missense_variant	Exon 3 of 11	1		ENSP00000421631.1
ADAMTS16	ENST00000433402.2	n.331G>T		non_coding_transcript_exon_variant	Exon 3 of 20	1
ENSG00000250866	ENST00000514848.1	n.221-3914C>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331G>T (p.D111Y) alteration is located in exon 3 (coding exon 3) of the ADAMTS16 gene. This alteration results from a G to T substitution at nucleotide position 331, causing the aspartic acid (D) at amino acid position 111 to be replaced by a tyrosine (Y). 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	0.16
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.92	P;D
Vest4		0.52
MutPred		0.53		Loss of disorder (P = 0.0216);Loss of disorder (P = 0.0216);
MVP		0.68
MPC		0.60
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.75
gMVP		0.55

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: rs766063759; hg19: chr5-5146398;