Genetic Variant NM_198994.3:c.1528_1530delGACinsCAT (chr20-2417423-GAC-CAT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_198994.3(TGM6):c.1528_1530delGACinsCAT (p.Asp510His) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TGM6
NM_198994.3 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.37

Publications

0 publications found

Variant links:

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)

TGM6 links:

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new If you want to explore the variant's impact on the transcript NM_198994.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (base 0.0001, raised to 0.000483 by highest known P/LP ClinVar AF 0.000483) — PM2 moderate.

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.1528_1530delGACinsCAT p.Asp510His	missense	N/A	Prot: NP_945345.2 UniProt: O95932-1
	TGM6 NM_001254734.2		c.1528_1530delGACinsCAT p.Asp510His	missense	N/A	Prot: NP_001241663.1 UniProt: O95932-2

TGM6 NM_198994.3

MANE Select

HGVSc / HGVSpc.1528_1530delGACinsCATp.Asp510His

Exon rankN/A

missense

Prot: NP_945345.2UniProt: O95932-1

TGM6 NM_001254734.2

HGVSc / HGVSpc.1528_1530delGACinsCATp.Asp510His

Exon rankN/A

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.1528_1530delGACinsCAT p.Asp510His	missense	N/A	Prot: ENSP00000202625.2 UniProt: O95932-1
	TGM6 ENST00000381423.1	TSL:1	c.1528_1530delGACinsCAT p.Asp510His	missense	N/A	Prot: ENSP00000370831.1 UniProt: O95932-2

TGM6 ENST00000202625.7

TSL:1MANE Select

HGVSc / HGVSpc.1528_1530delGACinsCATp.Asp510His

Exon rankN/A

missense

Prot: ENSP00000202625.2UniProt: O95932-1

TGM6 ENST00000381423.1

TSL:1

HGVSc / HGVSpc.1528_1530delGACinsCATp.Asp510His

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	5.4

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence