rs557817405

chr20-2431011-G-GAAC

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PM4_Supporting BP6_Very_Strong BS2

The NM_198994.3(TGM6):c.1953_1955dup(p.Gln652_Leu652insGln) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,614,054 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E651E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (3 hom.)
• Consequence: TGM6 NM_198994.3 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.81

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_198994.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 20-2431011-G-GAAC is Benign according to our data. Variant chr20-2431011-G-GAAC is described in ClinVar as [Likely_benign]. Clinvar id is 337937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM6	NM_198994.3	c.1953_1955dup	p.Gln652_Leu652insGln	inframe_insertion	12/13	ENST00000202625.7
TGM6	NM_001254734.2	c.1833+413_1833+415dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM6	ENST00000202625.7	c.1953_1955dup	p.Gln652_Leu652insGln	inframe_insertion	12/13	1	NM_198994.3	P1
TGM6	ENST00000381423.1	c.1833+413_1833+415dup		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152096 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00129 AC: 323 AN: 251154 Hom.: 0 AF XY: 0.00136 AC XY: 184 AN XY: 135710

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00215 AC: 3143 AN: 1461840 Hom.: 3 Cov.: 32 AF XY: 0.00203 AC XY: 1476 AN XY: 727222

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00270

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152214 Hom.: 2 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74428

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00130

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 13, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	TGM6: PM4:Supporting, BS1 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 13, 2016

- -

Autosomal dominant cerebellar ataxia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs557817405; hg19: chr20-2411657;