5-33549330-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_030955.4(ADAMTS12):c.4179C>G(p.Asp1393Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,614,116 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (20 hom.)
• Consequence: ADAMTS12 NM_030955.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073042214).
• BP6: Variant 5-33549330-G-C is Benign according to our data. Variant chr5-33549330-G-C is described in ClinVar as [Benign]. Clinvar id is 780955.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.007 (1066/152240) while in subpopulation AFR AF= 0.0243 (1009/41542). AF 95% confidence interval is 0.023. There are 10 homozygotes in gnomad4. There are 486 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS12	NM_030955.4	c.4179C>G	p.Asp1393Glu	missense_variant	21/24	ENST00000504830.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAMTS12	ENST00000504830.6	c.4179C>G	p.Asp1393Glu	missense_variant	21/24	1	NM_030955.4	P1
ADAMTS12	ENST00000352040.7	c.3924C>G	p.Asp1308Glu	missense_variant	19/22	1

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1066 AN: 152122 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00196 AC: 494 AN: 251404 Hom.: 6 AF XY: 0.00139 AC XY: 189 AN XY: 135880

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00130

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: 0.0000879

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000781 AC: 1142 AN: 1461876 Hom.: 20 Cov.: 31 AF XY: 0.000661 AC XY: 481 AN XY: 727242

Gnomad4 AFR exome AF: 0.0279

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00700 AC: 1066 AN: 152240 Hom.: 10 Cov.: 33 AF XY: 0.00653 AC XY: 486 AN XY: 74430

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00102 Hom.: 1

Bravo AF: 0.00762

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

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

Jul 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.028
Eigen_PC	Benign	0.055
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.69	T;T
MetaRNN	Benign	0.0073	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.16
Sift	Benign	0.059	T;T
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.77	P;B
Vest4		0.57
MutPred		0.20		Gain of disorder (P = 0.1503);.;
MVP		0.69
MPC		0.54
ClinPred		0.047	T
GERP RS		1.9
Varity_R		0.30
gMVP		0.41

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: rs61757473; hg19: chr5-33549435;