rs138184667

chr20-2417282-G-Achr20-2417282-G-C

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.1387G>A(p.Gly463Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,611,314 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0300

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=0.0054221153).
• BP6: Variant 20-2417282-G-A is Benign according to our data. Variant chr20-2417282-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 586815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM6	NM_198994.3	c.1387G>A	p.Gly463Ser	missense_variant	10/13	ENST00000202625.7
TGM6	NM_001254734.2	c.1387G>A	p.Gly463Ser	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM6	ENST00000202625.7	c.1387G>A	p.Gly463Ser	missense_variant	10/13	1	NM_198994.3	P1
TGM6	ENST00000381423.1	c.1387G>A	p.Gly463Ser	missense_variant	10/12	1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000203 AC: 49 AN: 241714 Hom.: 0 AF XY: 0.000114 AC XY: 15 AN XY: 131106

Gnomad AFR exome AF: 0.00286

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000692 AC: 101 AN: 1459036 Hom.: 0 Cov.: 32 AF XY: 0.0000565 AC XY: 41 AN XY: 725536

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74444

Gnomad4 AFR AF: 0.00284

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.000907

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000255 AC: 31

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 31, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	0.24
Dann	Benign	0.66
DEOGEN2	Benign	0.0017	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.020	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.19
Sift	Benign	0.37	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0020	B;B
Vest4		0.080
MVP		0.30
MPC		0.082
ClinPred		0.010	T
GERP RS		-9.1
Varity_R		0.032
gMVP		0.19

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: rs138184667; hg19: chr20-2397928; COSMIC: COSV52481104;