Genetic Variant TGM6:p.Pro26Thr (chr20-2394520-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_198994.3(TGM6):c.76C>A(p.Pro26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TGM6
NM_198994.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.497

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07458651).

BS2

High AC in GnomAdExome4 at 9 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.76C>A	p.Pro26Thr	missense_variant	Exon 2 of 13	ENST00000202625.7	NP_945345.2	O95932-1
TGM6	NM_001254734.2 link	c.76C>A	p.Pro26Thr	missense_variant	Exon 2 of 12		NP_001241663.1	O95932-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGM6	ENST00000202625.7 link	c.76C>A	p.Pro26Thr	missense_variant	Exon 2 of 13	1	NM_198994.3	ENSP00000202625.2	O95932-1
TGM6	ENST00000381423.1 link	c.76C>A	p.Pro26Thr	missense_variant	Exon 2 of 12	1		ENSP00000370831.1	O95932-2
TGM6	ENST00000477505.1 link	n.69C>A		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249976

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459586

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.0000224

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4272

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111832

Other (OTH)

AF:

0.00

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.0011

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.064

T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.26

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.075

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.0

M;M

PhyloP100

-0.50

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.77

N;N

REVEL

Uncertain

0.44

Sift

Benign

0.57

T;T

Sift4G

Benign

0.77

T;T

Polyphen

0.24

B;B

Vest4

0.12

MutPred

0.38

Loss of catalytic residue at P26 (P = 0.0019);Loss of catalytic residue at P26 (P = 0.0019);

MVP

0.59

MPC

0.093

ClinPred

0.11

GERP RS

3.5

Varity_R

0.14

gMVP

0.098

Mutation Taster

=91/9

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over