Genetic Variant ADAMTS4:p.Thr91Ala (chr1-161198357-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005099.6(ADAMTS4):c.271A>G(p.Thr91Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,613,114 control chromosomes in the GnomAD database, including 31 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T91M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 31 hom. )

Consequence

ADAMTS4
NM_005099.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.66

Variant links:

Genes affected

ADAMTS4 (HGNC:220): (ADAM metallopeptidase with thrombospondin type 1 motif 4) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of this 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 enzyme encoded by this gene lacks a C-terminal TS motif. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease is responsible for the degradation of aggrecan, a major proteoglycan of cartilage, and brevican, a brain-specific extracellular matrix protein. The expression of this gene is upregulated in arthritic disease and this may contribute to disease progression through the degradation of aggrecan. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ADAMTS4 links:

NDUFS2 (HGNC:7708): (NADH:ubiquinone oxidoreductase core subunit S2) The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

NDUFS2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006677747).

BP6

Variant 1-161198357-T-C is Benign according to our data. Variant chr1-161198357-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3898090.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAMTS4	NM_005099.6 link	c.271A>G	p.Thr91Ala	missense_variant	Exon 1 of 9	ENST00000367996.6	NP_005090.3	O75173-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAMTS4	ENST00000367996.6 link	c.271A>G	p.Thr91Ala	missense_variant	Exon 1 of 9	1	NM_005099.6	ENSP00000356975.4		O75173-1

Frequencies

GnomAD3 genomes

AF:

0.00403

AC:

612

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00648

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00607

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00403

AC:

995

AN:

247104

Hom.:

AF XY:

0.00406

AC XY:

546

AN XY:

134398

show subpopulations

Gnomad AFR exome

AF:

0.000960

Gnomad AMR exome

AF:

0.00337

Gnomad ASJ exome

AF:

0.00683

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00272

Gnomad FIN exome

AF:

0.00142

Gnomad NFE exome

AF:

0.00590

Gnomad OTH exome

AF:

0.00462

GnomAD4 exome

AF:

0.00491

AC:

7174

AN:

1460962

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

3504

AN XY:

726810

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00367

Gnomad4 ASJ exome

AF:

0.00724

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00307

Gnomad4 FIN exome

AF:

0.00163

Gnomad4 NFE exome

AF:

0.00556

Gnomad4 OTH exome

AF:

0.00431

GnomAD4 genome

AF:

0.00402

AC:

612

AN:

152152

Hom.:

Cov.:

AF XY:

0.00378

AC XY:

281

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000964

Gnomad4 AMR

AF:

0.00647

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.00123

Gnomad4 NFE

AF:

0.00607

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00554

Hom.:

Bravo

AF:

0.00436

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00582

AC:

ExAC

AF:

0.00399

AC:

484

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00486

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.061

T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.63

T;T

MetaRNN

Benign

0.0067

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.44

N;N

REVEL

Benign

0.068

Sift

Benign

0.79

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.0010

B;B

Vest4

0.13

MVP

0.45

MPC

0.31

ClinPred

0.0057

GERP RS

4.5

Varity_R

0.10

gMVP

0.25

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over