dbSNP rs748042241: TGM6:p.His509Gln (chr20-2417422-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198994.3(TGM6):c.1527C>A(p.His509Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H509H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TGM6
NM_198994.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.55

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.084747136).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM6	NM_198994.3 link	c.1527C>A	p.His509Gln	missense_variant	Exon 10 of 13	ENST00000202625.7	NP_945345.2	O95932-1
TGM6	NM_001254734.2 link	c.1527C>A	p.His509Gln	missense_variant	Exon 10 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.1527C>A	p.His509Gln	missense_variant	Exon 10 of 13	1	NM_198994.3	ENSP00000202625.2		O95932-1
TGM6	ENST00000381423.1 link	c.1527C>A	p.His509Gln	missense_variant	Exon 10 of 12	1		ENSP00000370831.1		O95932-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460702

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.58

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.016

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.48

T;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.085

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.14

N;N

PhyloP100

-1.5

PrimateAI

Benign

0.31

PROVEAN

Benign

1.0

N;N

REVEL

Benign

0.063

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0030

B;B

Vest4

0.18

MutPred

0.47

Loss of catalytic residue at D510 (P = 0.067);Loss of catalytic residue at D510 (P = 0.067);

MVP

0.26

MPC

0.085

ClinPred

0.039

GERP RS

-8.7

Varity_R

0.051

gMVP

0.25

Mutation Taster

=88/12

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