rs374219808

chr20-2417451-A-Cchr20-2417451-A-Gchr20-2417451-A-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_198994.3(TGM6):c.1556A>C(p.Asn519Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,611,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N519S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TGM6 NM_198994.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.61

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 20-2417451-A-C is Benign according to our data. Variant chr20-2417451-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448669.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM6	NM_198994.3	c.1556A>C	p.Asn519Thr	missense_variant	10/13	ENST00000202625.7
TGM6	NM_001254734.2	c.1556A>C	p.Asn519Thr	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM6	ENST00000202625.7	c.1556A>C	p.Asn519Thr	missense_variant	10/13	1	NM_198994.3	P1
TGM6	ENST00000381423.1	c.1556A>C	p.Asn519Thr	missense_variant	10/12	1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000768 AC: 19 AN: 247514 Hom.: 0 AF XY: 0.0000373 AC XY: 5 AN XY: 134130

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1459588 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 726164

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74390

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000319 Hom.: 0

Bravo AF: 0.000272

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2022

The c.1556A>C (p.N519T) alteration is located in exon 10 (coding exon 10) of the TGM6 gene. This alteration results from a A to C substitution at nucleotide position 1556, causing the asparagine (N) at amino acid position 519 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 23, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	0.72	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.97	D;D
Vest4		0.66
MVP		0.77
MPC		0.41
ClinPred		0.24	T
GERP RS		3.6
Varity_R		0.68
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs374219808; hg19: chr20-2398097;