14-24249390-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_000359.3(TGM1):c.2377G>A(p.Gly793Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: TGM1 NM_000359.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: -2.44

Genes affected

TGM1 (HGNC:11777): (transglutaminase 1) The protein encoded by this gene is a membrane protein that catalyzes the addition of an alkyl group from an akylamine to a glutamine residue of a protein, forming an alkylglutamine in the protein. This protein alkylation leads to crosslinking of proteins and catenation of polyamines to proteins. This gene contains either one or two copies of a 22 nt repeat unit in its 3' UTR. Mutations in this gene have been associated with autosomal recessive lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02632612).
• BP6: Variant 14-24249390-C-T is Benign according to our data. Variant chr14-24249390-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 991479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TGM1	NM_000359.3	c.2377G>A	p.Gly793Arg	missense_variant	15/15	ENST00000206765.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TGM1	ENST00000206765.11	c.2377G>A	p.Gly793Arg	missense_variant	15/15	1	NM_000359.3	P1
TGM1	ENST00000544573.5	c.1051G>A	p.Gly351Arg	missense_variant	9/9	2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000796 AC: 20 AN: 251342 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000917 AC: 134 AN: 1461832 Hom.: 0 Cov.: 34 AF XY: 0.0000811 AC XY: 59 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74452

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 17, 2020

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.011
Dann	Benign	0.40
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0045	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.085
Sift	Benign	0.52	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0	B;.
Vest4		0.12
MutPred		0.13		Loss of sheet (P = 0.0817);.;
MVP		0.40
MPC		0.31
ClinPred		0.044	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.031
gMVP		0.38

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: rs188646084; hg19: chr14-24718596;