rs80329336

Variant names:

• chr20-2380967-A-G
• rs80329336
• NM_198994.3:c.-2A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198994.3(TGM6):​c.-2A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000893 in 1,608,396 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (2 hom.)
• Consequence: TGM6 NM_198994.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.584
• Publications: 2 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 20-2380967-A-G is Benign according to our data. Variant chr20-2380967-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 337900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00439 (668/152278) while in subpopulation AFR AF = 0.0148 (617/41578). AF 95% confidence interval is 0.0139. There are 10 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 668 AD gene.

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.-2A>G		5_prime_UTR	Exon 1 of 13	NP_945345.2	O95932-1
	TGM6	NM_001254734.2		c.-2A>G		5_prime_UTR	Exon 1 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.-2A>G		5_prime_UTR	Exon 1 of 13	ENSP00000202625.2	O95932-1
	TGM6	ENST00000381423.1	TSL:1	c.-2A>G		5_prime_UTR	Exon 1 of 12	ENSP00000370831.1	O95932-2

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152160 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00122 AC: 292 AN: 239326 AF XY: 0.000946

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000687

Gnomad ASJ exome AF: 0.00135

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000921

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.000527 AC: 768 AN: 1456118 Hom.: 2 Cov.: 32 AF XY: 0.000488 AC XY: 353 AN XY: 723514

African (AFR) AF: 0.0161 AC: 538 AN: 33428

American (AMR) AF: 0.000659 AC: 29 AN: 43988

Ashkenazi Jewish (ASJ) AF: 0.00155 AC: 40 AN: 25860

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000475 AC: 4 AN: 84250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00292 AC: 15 AN: 5132

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1110518

Other (OTH) AF: 0.00150 AC: 90 AN: 60176

GnomAD4 genome AF: 0.00439 AC: 668 AN: 152278 Hom.: 10 Cov.: 32 AF XY: 0.00420 AC XY: 313 AN XY: 74440

African (AFR) AF: 0.0148 AC: 617 AN: 41578

American (AMR) AF: 0.00183 AC: 28 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00238 Hom.: 3

Bravo AF: 0.00549

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Spinocerebellar ataxia type 35 (1)
-	-	1	TGM6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.4
DANN	Benign	0.63
PhyloP100		-0.58
PromoterAI		0.042	Neutral
Mutation Taster		=300/0	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

Other links and lift over

dbSNP: rs80329336; hg19: chr20-2361613;