rs201326247

Positions:

• chr20-2403589-C-G
• chr20-2403589-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198994.3(TGM6):​c.1102C>G​(p.Arg368Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R368Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TGM6	NM_198994.3	c.1102C>G	p.Arg368Gly	missense_variant	9/13	ENST00000202625.7	NP_945345.2
TGM6	NM_001254734.2	c.1102C>G	p.Arg368Gly	missense_variant	9/12		NP_001241663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TGM6	ENST00000202625.7	c.1102C>G	p.Arg368Gly	missense_variant	9/13	1	NM_198994.3	ENSP00000202625.2
TGM6	ENST00000381423.1	c.1102C>G	p.Arg368Gly	missense_variant	9/12	1		ENSP00000370831.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.21	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.65	P;P
Vest4		0.37
MutPred		0.65		Loss of catalytic residue at R368 (P = 0.052);Loss of catalytic residue at R368 (P = 0.052);
MVP		0.75
MPC		0.17
ClinPred		0.89	D
GERP RS		3.9
Varity_R		0.17
gMVP		0.51

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: rs201326247; hg19: chr20-2384235;