rs148376598

Positions:

• chr20-2400411-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198994.3(TGM6):​c.956G>A​(p.Arg319Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,614,138 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.48

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015311629).
• BP6: Variant 20-2400411-G-A is Benign according to our data. Variant chr20-2400411-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212403.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 = 0.00114 (173/152264) while in subpopulation AFR AF= 0.00402 (167/41556). AF 95% confidence interval is 0.00352. There are 1 homozygotes in gnomad4. There are 96 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 173 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM6	NM_198994.3	c.956G>A	p.Arg319Gln	missense_variant	7/13	ENST00000202625.7	NP_945345.2
TGM6	NM_001254734.2	c.956G>A	p.Arg319Gln	missense_variant	7/12		NP_001241663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGM6	ENST00000202625.7	c.956G>A	p.Arg319Gln	missense_variant	7/13	1	NM_198994.3	ENSP00000202625.2
TGM6	ENST00000381423.1	c.956G>A	p.Arg319Gln	missense_variant	7/12	1		ENSP00000370831.1
TGM6	ENST00000477505.1	n.587G>A		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000287 AC: 72 AN: 251144 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135778

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000825 AC XY: 60 AN XY: 727236

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74444

Gnomad4 AFR AF: 0.00402

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.00125

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000296 AC: 36

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 23, 2019	- -

TGM6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.74	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.042	D;T
Polyphen		0.99	D;D
Vest4		0.42
MVP		0.81
MPC		0.43
ClinPred		0.056	T
GERP RS		4.4
Varity_R		0.22
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs148376598; hg19: chr20-2381057; COSMIC: COSV52482880;