20-2430472-T-C

Variant names:

• chr20-2430472-T-C
• rs142406714
• NM_198994.3:c.1705T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198994.3(TGM6):​c.1705T>C​(p.Tyr569His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. Y569N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• Publications: 0 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM6	NM_198994.3	c.1705T>C	p.Tyr569His	missense_variant	Exon 11 of 13	ENST00000202625.7	NP_945345.2
TGM6	NM_001254734.2	c.1705T>C	p.Tyr569His	missense_variant	Exon 11 of 12		NP_001241663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM6	ENST00000202625.7	c.1705T>C	p.Tyr569His	missense_variant	Exon 11 of 13	1	NM_198994.3	ENSP00000202625.2
TGM6	ENST00000381423.1	c.1705T>C	p.Tyr569His	missense_variant	Exon 11 of 12	1		ENSP00000370831.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.1	M;M
PhyloP100		4.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.67		Loss of catalytic residue at Y569 (P = 0.0058);Loss of catalytic residue at Y569 (P = 0.0058);
MVP		0.83
MPC		0.52
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.73
gMVP		0.56
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142406714; hg19: chr20-2411118;