5-33534889-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_030955.4(ADAMTS12):c.4550A>G(p.Lys1517Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000638 in 1,614,146 control chromosomes in the GnomAD database, including 8 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 0.0035 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: ADAMTS12 NM_030955.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.19

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029518902).
• BP6: Variant 5-33534889-T-C is Benign according to our data. Variant chr5-33534889-T-C is described in ClinVar as [Benign]. Clinvar id is 712571.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS12	NM_030955.4	c.4550A>G	p.Lys1517Arg	missense_variant	23/24	ENST00000504830.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS12	ENST00000504830.6	c.4550A>G	p.Lys1517Arg	missense_variant	23/24	1	NM_030955.4	P1
ADAMTS12	ENST00000352040.7	c.4295A>G	p.Lys1432Arg	missense_variant	21/22	1

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 538 AN: 152198 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000728 AC: 183 AN: 251378 Hom.: 1 AF XY: 0.000471 AC XY: 64 AN XY: 135864

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000336 AC: 491 AN: 1461830 Hom.: 3 Cov.: 30 AF XY: 0.000285 AC XY: 207 AN XY: 727222

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152316 Hom.: 5 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74492

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.00368

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00102 AC: 124

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.046
Sift	Benign	0.097	T;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.025	B;B
Vest4		0.088
MVP		0.51
MPC		0.14
ClinPred		0.022	T
GERP RS		0.98
Varity_R		0.11
gMVP		0.23

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: rs79764295; hg19: chr5-33534994;