chr20-2417489-A-C

Variant names:

• chr20-2417489-A-C
• NM_198994.3:c.1594A>C
• TGM6 p.Ser532Arg

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198994.3(TGM6):​c.1594A>C​(p.Ser532Arg) 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. Synonymous variant affecting the same amino acid position (i.e. S532S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.34
• 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: Orphanet, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

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.1594A>C	p.Ser532Arg	missense	Exon 10 of 13	NP_945345.2	O95932-1
	TGM6	NM_001254734.2		c.1594A>C	p.Ser532Arg	missense	Exon 10 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.1594A>C	p.Ser532Arg	missense	Exon 10 of 13	ENSP00000202625.2	O95932-1
	TGM6	ENST00000381423.1	TSL:1	c.1594A>C	p.Ser532Arg	missense	Exon 10 of 12	ENSP00000370831.1	O95932-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.28	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.53
Sift	Benign	0.091	T
Sift4G	Benign	0.12	T
Varity_R		0.67
gMVP		0.68
Mutation Taster		=80/20	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr20-2398135;

COSMIC: COSV52485244;