NM_198994.3:c.1171G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBS1BS2_Supporting

The NM_198994.3(TGM6):c.1171G>A(p.Val391Met) variant causes a missense change. The variant allele was found at a frequency of 0.000328 in 1,614,162 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V391L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 8 hom. )

Consequence

TGM6
NM_198994.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 4.35

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 35
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Orphanet

TGM6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02161333).

BP6

Variant 20-2403658-G-A is Benign according to our data. Variant chr20-2403658-G-A is described in ClinVar as Benign. ClinVar VariationId is 337923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000374 (57/152290) while in subpopulation EAS AF = 0.00869 (45/5180). AF 95% confidence interval is 0.00667. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 57 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM6	NM_198994.3 link	c.1171G>A	p.Val391Met	missense_variant	Exon 9 of 13	ENST00000202625.7	NP_945345.2	O95932-1
TGM6	NM_001254734.2 link	c.1171G>A	p.Val391Met	missense_variant	Exon 9 of 12		NP_001241663.1	O95932-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM6	ENST00000202625.7 link	c.1171G>A	p.Val391Met	missense_variant	Exon 9 of 13	1	NM_198994.3	ENSP00000202625.2		O95932-1
TGM6	ENST00000381423.1 link	c.1171G>A	p.Val391Met	missense_variant	Exon 9 of 12	1		ENSP00000370831.1		O95932-2

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00867

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000815

AC:

205

AN:

251454

AF XY:

0.000728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00962

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000324

AC:

473

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

225

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00924

AC:

367

AN:

39700

South Asian (SAS)

AF:

0.000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1112010

Other (OTH)

AF:

0.000447

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000374

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41556

American (AMR)

AF:

0.000196

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00869

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000501

Hom.:

Bravo

AF:

0.000665

ExAC

AF:

0.000898

AC:

109

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 35

Uncertain:1Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 22, 2021

O&I group, Department of Genetics, University Medical Center of Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

not specified

Benign:1

Nov 15, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.084

T;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.022

T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

4.4

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.2

N;N

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0050

D;T

Polyphen

1.0

D;D

Vest4

0.71

MVP

0.69

MPC

0.44

ClinPred

0.045

GERP RS

4.9

Varity_R

0.39

gMVP

0.51

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over