rs147494925

Positions:

chr20-2396583-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198994.3(TGM6):c.502G>A(p.Val168Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,614,224 control chromosomes in the GnomAD database, including 3 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 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

TGM6
NM_198994.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

TGM6 (HGNC:16255): (transglutaminase 6) The protein encoded by this gene belongs to the transglutaminase superfamily. It catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Mutations in this gene are associated with spinocerebellar ataxia type 35 (SCA35). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

TGM6 links:

TGM6 (HGNC:):

TGM6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012268782).

BP6

Variant 20-2396583-G-A is Benign according to our data. Variant chr20-2396583-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 448677.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 = 0.00161 (246/152338) while in subpopulation AFR AF= 0.00536 (223/41584). AF 95% confidence interval is 0.00479. There are 2 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 246 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM6	NM_198994.3 linkuse as main transcript	c.502G>A	p.Val168Met	missense_variant	4/13	ENST00000202625.7	NP_945345.2	O95932-1
TGM6	NM_001254734.2 linkuse as main transcript	c.502G>A	p.Val168Met	missense_variant	4/12		NP_001241663.1	O95932-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TGM6	ENST00000202625.7 linkuse as main transcript	c.502G>A	p.Val168Met	missense_variant	4/13	1	NM_198994.3	ENSP00000202625.2	O95932-1
TGM6	ENST00000381423.1 linkuse as main transcript	c.502G>A	p.Val168Met	missense_variant	4/12	1		ENSP00000370831.1	O95932-2
TGM6	ENST00000477505.1 linkuse as main transcript	n.175-1335G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

247

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00538

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000382

AC:

AN:

251394

Hom.:

AF XY:

0.000353

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.000318

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:

0.0000440

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000162

AC:

237

AN:

1461886

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

121

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00502

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.00161

AC:

246

AN:

152338

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

110

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00536

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000851

Hom.:

Bravo

AF:

0.00185

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000478

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TGM6: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Oct 19, 2017	BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

TGM6-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2020

This variant is classified as 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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0045

T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Benign

0.17

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.012

T;T

MetaSVM

Uncertain

-0.044

MutationAssessor

Benign

1.9

L;L

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.040

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.097

T;T

Sift4G

Benign

0.25

T;T

Polyphen

1.0

D;D

Vest4

0.52

MVP

0.47

MPC

0.34

ClinPred

0.022

GERP RS

5.1

Varity_R

0.073

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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