chr5-129461122-C-G

Position:

chr5-129461122-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_133638.6(ADAMTS19):c.112C>G(p.Arg38Gly) 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 1,420,116 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 5 hom. )

Consequence

ADAMTS19
NM_133638.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.235

Variant links:

Genes affected

ADAMTS19 (HGNC:17111): (ADAM metallopeptidase with thrombospondin type 1 motif 19) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motif) 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 protein encoded by this gene has high sequence similarity to the protein encoded by ADAMTS16, another family member. [provided by RefSeq, Jul 2008]

ADAMTS19 links:

ADAMTS19-AS1 (HGNC:40797): (ADAMTS19 antisense RNA 1)

ADAMTS19-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009558201).

BP6

Variant 5-129461122-C-G is Benign according to our data. Variant chr5-129461122-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2362481.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00164 (249/152260) while in subpopulation NFE AF= 0.00303 (206/67996). AF 95% confidence interval is 0.00269. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAMTS19	NM_133638.6 linkuse as main transcript	c.112C>G	p.Arg38Gly	missense_variant	2/23	ENST00000274487.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ADAMTS19	ENST00000274487.9 linkuse as main transcript	c.112C>G	p.Arg38Gly	missense_variant	2/23	1	NM_133638.6	P1
ADAMTS19	ENST00000505791.5 linkuse as main transcript	c.91+640C>G		intron_variant, NMD_transcript_variant		3
ADAMTS19-AS1	ENST00000661962.1 linkuse as main transcript			upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00303

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00112

AC:

AN:

63658

Hom.:

AF XY:

0.000892

AC XY:

AN XY:

36990

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.000637

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000380

Gnomad NFE exome

AF:

0.00277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00295

AC:

3739

AN:

1267856

Hom.:

Cov.:

AF XY:

0.00276

AC XY:

1723

AN XY:

623788

show subpopulations

Gnomad4 AFR exome

AF:

0.000312

Gnomad4 AMR exome

AF:

0.000928

Gnomad4 ASJ exome

AF:

0.0000944

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000542

Gnomad4 NFE exome

AF:

0.00353

Gnomad4 OTH exome

AF:

0.00198

GnomAD4 genome

AF:

0.00164

AC:

249

AN:

152260

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00303

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000735

Hom.:

Bravo

AF:

0.00170

ExAC

AF:

0.000411

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2021

The c.94C>G (p.R32G) alteration is located in exon 2 (coding exon 2) of the ADAMTS19 gene. This alteration results from a C to G substitution at nucleotide position 94, causing the arginine (R) at amino acid position 32 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ADAMTS19-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.74

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.0096

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

REVEL

Benign

0.10

Polyphen

0.0

.;B

MVP

0.068

MPC

1.8

ClinPred

0.015

GERP RS

3.1

Varity_R

0.13

gMVP

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over