rs144338465

chr20-2403703-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_198994.3(TGM6):c.1216G>A(p.Glu406Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,614,196 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.116

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010067344).
• BP6: Variant 20-2403703-G-A is Benign according to our data. Variant chr20-2403703-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 337924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-2403703-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 191 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM6	NM_198994.3	c.1216G>A	p.Glu406Lys	missense_variant	9/13	ENST00000202625.7
TGM6	NM_001254734.2	c.1216G>A	p.Glu406Lys	missense_variant	9/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM6	ENST00000202625.7	c.1216G>A	p.Glu406Lys	missense_variant	9/13	1	NM_198994.3	P1
TGM6	ENST00000381423.1	c.1216G>A	p.Glu406Lys	missense_variant	9/12	1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 191 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

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: 0.00273

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00135 AC: 339 AN: 251452 Hom.: 0 AF XY: 0.00121 AC XY: 164 AN XY: 135914

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00201 AC: 2945 AN: 1461876 Hom.: 6 Cov.: 32 AF XY: 0.00186 AC XY: 1351 AN XY: 727240

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.00237

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74472

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00155 Hom.: 0

Bravo AF: 0.00108

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00132 AC: 160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TGM6: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Feb 09, 2017

- -

Spinocerebellar ataxia type 35 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	11
Dann	Benign	0.96
DEOGEN2	Benign	0.0026	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.12	N;N
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.11
Sift	Benign	0.57	T;T
Sift4G	Benign	0.83	T;T
Polyphen		0.0020	B;B
Vest4		0.18
MVP		0.43
MPC		0.093
ClinPred		0.0049	T
GERP RS		3.9
Varity_R		0.059
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs144338465; hg19: chr20-2384349;