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14-24249373-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_000359.3(TGM1):c.2394C>T(p.Asp798=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

TGM1
NM_000359.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, single submitter U:1B:1

Conservation

PhyloP100: -2.21
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-24249373-G-A is Benign according to our data. Variant chr14-24249373-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 991478.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-2.21 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TGM1NM_000359.3 linkuse as main transcriptc.2394C>T p.Asp798= synonymous_variant 15/15 ENST00000206765.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TGM1ENST00000206765.11 linkuse as main transcriptc.2394C>T p.Asp798= synonymous_variant 15/151 NM_000359.3 P1P22735-1
TGM1ENST00000544573.5 linkuse as main transcriptc.1068C>T p.Asp356= synonymous_variant 9/92 P22735-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000138
AC:
21
AN:
152078
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000322
AC:
81
AN:
251304
Hom.:
0
AF XY:
0.000243
AC XY:
33
AN XY:
135852
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00130
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000870
Gnomad SAS exome
AF:
0.000359
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000999
AC:
146
AN:
1461812
Hom.:
0
Cov.:
34
AF XY:
0.0000866
AC XY:
63
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00121
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000479
Gnomad4 SAS exome
AF:
0.000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000423
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000138
AC:
21
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74408
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000622
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000141
Hom.:
0
Bravo
AF:
0.000136
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000327
EpiControl
AF:
0.000119

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Apr 17, 2020- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 26, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.93
Cadd
Benign
0.072
Dann
Benign
0.19
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs201811993; hg19: chr14-24718579; COSMIC: COSV52865744; COSMIC: COSV52865744; API