20-2417423-G-C

Variant names:

• chr20-2417423-G-C
• rs201964784
• NM_198994.3:c.1528G>C
• TGM6 p.Asp510His

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019).

The NM_198994.3(TGM6):c.1528G>C (p.Asp510His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000316 (AC=51) in the gnomAD database across 1,612,992 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00105. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 2.44
• Publications: 12 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)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 28 criteria.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TGM6 NM_198994.3	MANE Select	c.1528G>C p.Asp510His	missense	Exon 10 of 13	Prot: NP_945345.2 UniProt:
	TGM6 NM_001254734.2		c.1528G>C p.Asp510His	missense	Exon 10 of 12	Prot: NP_001241663.1 UniProt:

TGM6 NM_198994.3

MANE Select

HGVSc / HGVSpc.1528G>Cp.Asp510His

Exon rankExon 10 of 13

missense

Prot: NP_945345.2UniProt: O95932-1

TGM6 NM_001254734.2

HGVSc / HGVSpc.1528G>Cp.Asp510His

Exon rankExon 10 of 12

missense

Prot: NP_001241663.1UniProt: O95932-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TGM6 ENST00000202625.7	TSL:1MANE Select	c.1528G>C p.Asp510His	missense	Exon 10 of 13	Prot: ENSP00000202625.2 UniProt:
	TGM6 ENST00000381423.1	TSL:1	c.1528G>C p.Asp510His	missense	Exon 10 of 12	Prot: ENSP00000370831.1 UniProt:

TGM6 ENST00000202625.7

TSL:1MANE Select

HGVSc / HGVSpc.1528G>Cp.Asp510His

Exon rankExon 10 of 13

missense

Prot: ENSP00000202625.2UniProt: O95932-1

TGM6 ENST00000381423.1

TSL:1

HGVSc / HGVSpc.1528G>Cp.Asp510His

Exon rankExon 10 of 12

missense

Prot: ENSP00000370831.1UniProt: O95932-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000657	AC:10	Hom:0	AN:152218	Cov:32
GnomAD2 exomes	AF: 0.000148	AC:37	Hom:	AN:249568	Cov:
GnomAD4 exome	AF: 0.0000281	AC:41	Hom:0	AN:1460656	Cov:33
GnomAD4 genome	AF: 0.0000656	AC:10	Hom:0	AN:152336	Cov:32
TOPMed (Bravo)	AF: 0.0000680	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.000542	AC:	Hom:	AN:	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00	AC:0	Hom:0	AN:122614	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00257	AC:23	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.000119	5	41958	0.000120	8	66888
SCHEMA(Schizophrenia)	0.000253	26	102712	0.000158	29	183402

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	-	Spinocerebellar ataxia type 35 (2)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.81	D
FuncVEP CTI	Pathogenic	0.98
GPN-Star LLR	N/A	-6.5
GPN-Star score	N/A	6.5
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.0088	T
Mutation Taster	N/A	30/70	disease causing (ClinVar)
MutationAssessor	Pathogenic	2.9	M
PhyloP100	Benign	2.4
popEVE	Benign	-3.5
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Varity_R	N/A	0.93
VESM-3B	Benign	-7.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs201964784;

hg19: chr20-2398069;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar