chr20-2417423-G-A

Variant names:

• chr20-2417423-G-A
• rs201964784
• NM_198994.3:c.1528G>A
• TGM6 p.Asp510Asn

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4

The NM_198994.3(TGM6):c.1528G>A (p.Asp510Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000685 (AC=1) in the gnomAD database across 1,460,656 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000685. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.D510H: Uncertain_significance (ClinVar VariationId 42023, 2 stars)

• 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: 2.44
• Publications: 9 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 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000685 — very rare for AD/XL gene (base 0.0001, raised to 0.000483 by highest known P/LP ClinVar AF 0.000483) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

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>A p.Asp510Asn	missense	Exon 10 of 13	Prot: NP_945345.2 UniProt:
	TGM6 NM_001254734.2		c.1528G>A p.Asp510Asn	missense	Exon 10 of 12	Prot: NP_001241663.1 UniProt:

TGM6 NM_198994.3

MANE Select

HGVSc / HGVSpc.1528G>Ap.Asp510Asn

Exon rankExon 10 of 13

missense

Prot: NP_945345.2UniProt: O95932-1

TGM6 NM_001254734.2

HGVSc / HGVSpc.1528G>Ap.Asp510Asn

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>A p.Asp510Asn	missense	Exon 10 of 13	Prot: ENSP00000202625.2 UniProt:
	TGM6 ENST00000381423.1	TSL:1	c.1528G>A p.Asp510Asn	missense	Exon 10 of 12	Prot: ENSP00000370831.1 UniProt:

TGM6 ENST00000202625.7

TSL:1MANE Select

HGVSc / HGVSpc.1528G>Ap.Asp510Asn

Exon rankExon 10 of 13

missense

Prot: ENSP00000202625.2UniProt: O95932-1

TGM6 ENST00000381423.1

TSL:1

HGVSc / HGVSpc.1528G>Ap.Asp510Asn

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:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000401	AC:1	Hom:	AN:249568	Cov:
GnomAD4 exome	AF: 6.85e-7	AC:1	Hom:0	AN:1460656	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	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: 0.000148	AC:	Hom:	AN:	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000730	AC:9	Hom:0	AN:122614	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000389	4	102712	0.0000273	5	183402

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.74	D
FuncVEP CTI	Pathogenic	0.54
GPN-Star LLR	N/A	-3.9
GPN-Star score	N/A	3.9
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.31	T
Mutation Taster	N/A	83/17	polymorphism
MutationAssessor	Uncertain	2.0	M
PhyloP100	Benign	2.4
popEVE	Benign	-3.2
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Varity_R	N/A	0.46
VESM-3B	Benign	-5.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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