rs147494925

Positions:

• chr20-2396583-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.502G>A​(p.Val168Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,614,224 control chromosomes in the GnomAD database, including 3 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 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012268782).
• BP6: Variant 20-2396583-G-A is Benign according to our data. Variant chr20-2396583-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 448677.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 = 0.00161 (246/152338) while in subpopulation AFR AF= 0.00536 (223/41584). AF 95% confidence interval is 0.00479. There are 2 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 246 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM6	NM_198994.3	c.502G>A	p.Val168Met	missense_variant	4/13	ENST00000202625.7
TGM6	NM_001254734.2	c.502G>A	p.Val168Met	missense_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM6	ENST00000202625.7	c.502G>A	p.Val168Met	missense_variant	4/13	1	NM_198994.3	P1
TGM6	ENST00000381423.1	c.502G>A	p.Val168Met	missense_variant	4/12	1
TGM6	ENST00000477505.1	n.175-1335G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152220 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251394 Hom.: 1 AF XY: 0.000353 AC XY: 48 AN XY: 135872

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461886 Hom.: 1 Cov.: 31 AF XY: 0.000166 AC XY: 121 AN XY: 727246

Gnomad4 AFR exome AF: 0.00502

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00161 AC: 246 AN: 152338 Hom.: 2 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74492

Gnomad4 AFR AF: 0.00536

Gnomad4 AMR AF: 0.00124

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: 0.00142

Alfa AF: 0.000851 Hom.: 0

Bravo AF: 0.00185

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000478 AC: 58

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TGM6: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Oct 19, 2017	BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

TGM6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2020

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0045	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.040	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.097	T;T
Sift4G	Benign	0.25	T;T
Polyphen		1.0	D;D
Vest4		0.52
MVP		0.47
MPC		0.34
ClinPred		0.022	T
GERP RS		5.1
Varity_R		0.073
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs147494925; hg19: chr20-2377229; COSMIC: COSV52477239;