20-2394456-C-G

Variant summary

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

The NM_198994.3(TGM6):c.12C>G(p.Ile4Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,611,474 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 5 hom. )

Consequence

TGM6
NM_198994.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.265

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:

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=0.007067114).

BP6

Variant 20-2394456-C-G is Benign according to our data. Variant chr20-2394456-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 337901.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 = 0.00402 (613/152334) while in subpopulation AFR AF= 0.0141 (587/41578). AF 95% confidence interval is 0.0132. There are 4 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd at 611 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM6	NM_198994.3 linkuse as main transcript	c.12C>G	p.Ile4Met	missense_variant	2/13	ENST00000202625.7
TGM6	NM_001254734.2 linkuse as main transcript	c.12C>G	p.Ile4Met	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM6	ENST00000202625.7 linkuse as main transcript	c.12C>G	p.Ile4Met	missense_variant	2/13	1	NM_198994.3	P1	O95932-1
TGM6	ENST00000381423.1 linkuse as main transcript	c.12C>G	p.Ile4Met	missense_variant	2/12	1			O95932-2
TGM6	ENST00000477505.1 linkuse as main transcript	n.5C>G		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes

AF:

0.00401

AC:

611

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0141

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.0000441

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00105

AC:

260

AN:

248366

Hom.:

AF XY:

0.000684

AC XY:

AN XY:

134590

show subpopulations

Gnomad AFR exome

AF:

0.0142

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000539

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000486

AC:

709

AN:

1459140

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

293

AN XY:

725890

show subpopulations

Gnomad4 AFR exome

AF:

0.0166

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00125

GnomAD4 genome

AF:

0.00402

AC:

613

AN:

152334

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0141

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.00498

ESP6500AA

AF:

0.0154

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00133

AC:

161

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 08, 2022	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	TGM6: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 26, 2020

- -

TGM6-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 04, 2022

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). -

Spinocerebellar ataxia type 35

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.0041

T;.

Eigen

Benign

-0.018

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.52

T;T

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.52

N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.66

P;P

Vest4

0.094

MVP

0.61

MPC

0.21

ClinPred

0.011

GERP RS

4.5

Varity_R

0.32

gMVP

0.083

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