20-2394456-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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

Publications

1 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: PanelApp Australia, Orphanet, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)

TGM6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 613 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198994.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM6	NM_198994.3	MANE Select	c.12C>G	p.Ile4Met	missense	Exon 2 of 13	NP_945345.2	O95932-1
	TGM6	NM_001254734.2		c.12C>G	p.Ile4Met	missense	Exon 2 of 12	NP_001241663.1	O95932-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGM6	ENST00000202625.7	TSL:1 MANE Select	c.12C>G	p.Ile4Met	missense	Exon 2 of 13	ENSP00000202625.2	O95932-1
TGM6	ENST00000381423.1	TSL:1	c.12C>G	p.Ile4Met	missense	Exon 2 of 12	ENSP00000370831.1	O95932-2
TGM6	ENST00000477505.1	TSL:5	n.5C>G		non_coding_transcript_exon	Exon 1 of 4

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

GnomAD2 exomes

AF:

0.00105

AC:

260

AN:

248366

AF XY:

0.000684

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 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

African (AFR)

AF:

0.0166

AC:

555

AN:

33406

American (AMR)

AF:

0.000693

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52868

Middle Eastern (MID)

AF:

0.00266

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.0000306

AC:

AN:

1111820

Other (OTH)

AF:

0.00125

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00402

AC:

613

AN:

152334

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0141

AC:

587

AN:

41578

American (AMR)

AF:

0.00105

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Spinocerebellar ataxia type 35 (1)

TGM6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0041

Eigen

Benign

-0.018

Eigen_PC

Benign

-0.011

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.2

PhyloP100

0.27

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.52

REVEL

Uncertain

0.37

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0090

Polyphen

0.66

Vest4

0.094

MVP

0.61

MPC

0.21

ClinPred

0.011

GERP RS

4.5

Varity_R

0.32

gMVP

0.083

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over