NM_198994.3:c.12C>G

Variant names:

• chr20-2394456-C-G
• rs139796716
• NM_198994.3:c.12C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198994.3(TGM6):​c.12C>G​(p.Ile4Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,611,474 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (5 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.265
• Publications: 1 publications found

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: PanelApp Australia, Orphanet, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007067114).
• BP6: Variant 20-2394456-C-G is Benign according to our data. Variant chr20-2394456-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 337901.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 = 0.00402 (613/152334) while in subpopulation AFR AF = 0.0141 (587/41578). AF 95% confidence interval is 0.0132. There are 4 homozygotes in GnomAd4. There are 289 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 613 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198994.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM6	NM_198994.3	MANE Select	c.12C>G	p.Ile4Met	missense	Exon 2 of 13	NP_945345.2	O95932-1
	TGM6	NM_001254734.2		c.12C>G	p.Ile4Met	missense	Exon 2 of 12	NP_001241663.1	O95932-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM6	ENST00000202625.7	TSL:1 MANE Select	c.12C>G	p.Ile4Met	missense	Exon 2 of 13	ENSP00000202625.2	O95932-1
	TGM6	ENST00000381423.1	TSL:1	c.12C>G	p.Ile4Met	missense	Exon 2 of 12	ENSP00000370831.1	O95932-2
	TGM6	ENST00000477505.1	TSL:5	n.5C>G		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 611 AN: 152216 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0141

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00105 AC: 260 AN: 248366 AF XY: 0.000684

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000539

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000486 AC: 709 AN: 1459140 Hom.: 5 Cov.: 30 AF XY: 0.000404 AC XY: 293 AN XY: 725890

African (AFR) AF: 0.0166 AC: 555 AN: 33406

American (AMR) AF: 0.000693 AC: 31 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52868

Middle Eastern (MID) AF: 0.00266 AC: 11 AN: 4142

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111820

Other (OTH) AF: 0.00125 AC: 75 AN: 60200

GnomAD4 genome AF: 0.00402 AC: 613 AN: 152334 Hom.: 4 Cov.: 32 AF XY: 0.00388 AC XY: 289 AN XY: 74498

African (AFR) AF: 0.0141 AC: 587 AN: 41578

American (AMR) AF: 0.00105 AC: 16 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00498

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00133 AC: 161

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Spinocerebellar ataxia type 35 (1)
-	-	1	TGM6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.27
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.66	P
Vest4		0.094
MVP		0.61
MPC		0.21
ClinPred		0.011	T
GERP RS		4.5
Varity_R		0.32
gMVP		0.083
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs139796716; hg19: chr20-2375102; COSMIC: COSV99060587;