chr5-33549330-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 10 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 20 hom. )

Consequence

ADAMTS12
NM_030955.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.24

Publications

4 publications found

Variant links:

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]

ADAMTS12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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/Likely_benign. ClinVar VariationId is 780955.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 = 0.007 (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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030955.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS12	NM_030955.4	MANE Select	c.4179C>G	p.Asp1393Glu	missense	Exon 21 of 24	NP_112217.2	P58397-1
	ADAMTS12	NM_001324512.2		c.3924C>G	p.Asp1308Glu	missense	Exon 19 of 22	NP_001311441.1	P58397-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAMTS12	ENST00000504830.6	TSL:1 MANE Select	c.4179C>G	p.Asp1393Glu	missense	Exon 21 of 24	ENSP00000422554.1	P58397-1
	ADAMTS12	ENST00000352040.7	TSL:1	c.3924C>G	p.Asp1308Glu	missense	Exon 19 of 22	ENSP00000344847.3	P58397-3

Frequencies

GnomAD3 genomes

AF:

0.00701

AC:

1066

AN:

152122

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00196

AC:

494

AN:

251404

AF XY:

0.00139

show subpopulations

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 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.:

Cov.:

AF XY:

0.000661

AC XY:

481

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0279

AC:

935

AN:

33478

American (AMR)

AF:

0.00130

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1112000

Other (OTH)

AF:

0.00171

AC:

103

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

129

193

258

322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00700

AC:

1066

AN:

152240

Hom.:

Cov.:

AF XY:

0.00653

AC XY:

486

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0243

AC:

1009

AN:

41542

American (AMR)

AF:

0.00275

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00762

ESP6500AA

AF:

0.0243

AC:

107

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00229

AC:

278

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

0.028

Eigen_PC

Benign

0.055

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0073

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.7

PhyloP100

1.2

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.16

Sift

Benign

0.059

Sift4G

Uncertain

0.0030

Polyphen

0.77

Vest4

0.57

MutPred

0.20

Gain of disorder (P = 0.1503)

MVP

0.69

MPC

0.54

ClinPred

0.047

GERP RS

1.9

Varity_R

0.30

gMVP

0.41

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over