NM_198994.3:c.1596C>A

Variant names:

• chr20-2417491-C-A
• rs762016624
• NM_198994.3:c.1596C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198994.3(TGM6):​c.1596C>A​(p.Ser532Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,462 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S532S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.68
• Publications: 0 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: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM6	NM_198994.3	c.1596C>A	p.Ser532Arg	missense_variant	Exon 10 of 13	ENST00000202625.7	NP_945345.2
TGM6	NM_001254734.2	c.1596C>A	p.Ser532Arg	missense_variant	Exon 10 of 12		NP_001241663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM6	ENST00000202625.7	c.1596C>A	p.Ser532Arg	missense_variant	Exon 10 of 13	1	NM_198994.3	ENSP00000202625.2
TGM6	ENST00000381423.1	c.1596C>A	p.Ser532Arg	missense_variant	Exon 10 of 12	1		ENSP00000370831.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456462 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 724696

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	5.3
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		-1.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.46
Sift	Benign	0.091	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.83	P;P
Vest4		0.60
MutPred		0.69		Gain of methylation at S532 (P = 0.0087);Gain of methylation at S532 (P = 0.0087);
MVP		0.32
MPC		0.17
ClinPred		0.94	D
GERP RS		-2.7
Varity_R		0.64
gMVP		0.68
Mutation Taster		=88/12	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: rs762016624; hg19: chr20-2398137;