5-65224338-T-C

Position:

• chr5-65224338-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_197941.4(ADAMTS6):​c.2254A>G​(p.Met752Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,614,074 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (43 hom.)
• Consequence: ADAMTS6 NM_197941.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.323

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023409426).
• BP6: Variant 5-65224338-T-C is Benign according to our data. Variant chr5-65224338-T-C is described in ClinVar as [Benign]. Clinvar id is 786057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2062/152310) while in subpopulation AFR AF= 0.0458 (1903/41566). AF 95% confidence interval is 0.0441. There are 41 homozygotes in gnomad4. There are 957 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2062 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAMTS6	NM_197941.4	c.2254A>G	p.Met752Val	missense_variant	18/25	ENST00000381055.8	NP_922932.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAMTS6	ENST00000381055.8	c.2254A>G	p.Met752Val	missense_variant	18/25	1	NM_197941.4	ENSP00000370443.3

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2061 AN: 152192 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00398 AC: 1000 AN: 251406 Hom.: 16 AF XY: 0.00302 AC XY: 411 AN XY: 135870

Gnomad AFR exome AF: 0.0452

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00565

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00169 AC: 2476 AN: 1461764 Hom.: 43 Cov.: 30 AF XY: 0.00154 AC XY: 1123 AN XY: 727176

Gnomad4 AFR exome AF: 0.0468

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.0135 AC: 2062 AN: 152310 Hom.: 41 Cov.: 32 AF XY: 0.0128 AC XY: 957 AN XY: 74490

Gnomad4 AFR AF: 0.0458

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00263 Hom.: 11

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0465 AC: 205

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00479 AC: 581

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 04, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.2
DANN	Benign	0.62
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.72	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	0.98	T
Polyphen		0.0	B
Vest4		0.28
MVP		0.13
MPC		0.50
ClinPred		0.0018	T
GERP RS		-3.0
Varity_R		0.036
gMVP		0.39

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: rs77712043; hg19: chr5-64520165;