14-24249309-G-A

Variant names:

• chr14-24249309-G-A
• rs2229463
• NM_000359.3:c.*4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000359.3(TGM1):​c.*4C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 1,612,060 control chromosomes in the GnomAD database, including 552,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48257 hom., cov: 29)
  • Exomes 𝑓: 0.83 (504242 hom.)
• Consequence: TGM1 NM_000359.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.265

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-24249309-G-A is Benign according to our data. Variant chr14-24249309-G-A is described in ClinVar as [Benign]. Clinvar id is 1342288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-24249309-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM1	NM_000359.3	c.*4C>T		3_prime_UTR_variant	Exon 15 of 15	ENST00000206765.11	NP_000350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM1	ENST00000206765.11	c.*4C>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_000359.3	ENSP00000206765.6
TGM1	ENST00000544573.5	c.*4C>T		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000439446.1

Frequencies

GnomAD3 genomes AF: 0.793 AC: 120408 AN: 151856 Hom.: 48238 Cov.: 29

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.839

Gnomad ASJ AF: 0.900

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.817

GnomAD2 exomes AF: 0.796 AC: 199266 AN: 250274 AF XY: 0.794

Gnomad AFR exome AF: 0.697

Gnomad AMR exome AF: 0.856

Gnomad ASJ exome AF: 0.892

Gnomad EAS exome AF: 0.584

Gnomad FIN exome AF: 0.761

Gnomad NFE exome AF: 0.855

Gnomad OTH exome AF: 0.829

GnomAD4 exome AF: 0.828 AC: 1208850 AN: 1460086 Hom.: 504242 Cov.: 40 AF XY: 0.825 AC XY: 599012 AN XY: 726372

African (AFR) AF: 0.699 AC: 23409 AN: 33468

American (AMR) AF: 0.855 AC: 38214 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 23261 AN: 26132

East Asian (EAS) AF: 0.552 AC: 21907 AN: 39700

South Asian (SAS) AF: 0.678 AC: 58494 AN: 86220

European-Finnish (FIN) AF: 0.766 AC: 40013 AN: 52240

Middle Eastern (MID) AF: 0.882 AC: 5083 AN: 5766

European-Non Finnish (NFE) AF: 0.854 AC: 948711 AN: 1111480

Other (OTH) AF: 0.824 AC: 49758 AN: 60360

GnomAD4 genome AF: 0.793 AC: 120476 AN: 151974 Hom.: 48257 Cov.: 29 AF XY: 0.786 AC XY: 58342 AN XY: 74268

African (AFR) AF: 0.706 AC: 29239 AN: 41420

American (AMR) AF: 0.838 AC: 12815 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 3122 AN: 3468

East Asian (EAS) AF: 0.572 AC: 2940 AN: 5138

South Asian (SAS) AF: 0.667 AC: 3202 AN: 4800

European-Finnish (FIN) AF: 0.767 AC: 8114 AN: 10576

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.857 AC: 58216 AN: 67964

Other (OTH) AF: 0.818 AC: 1727 AN: 2110

Alfa AF: 0.838 Hom.: 151052

Bravo AF: 0.797

Asia WGS AF: 0.649 AC: 2256 AN: 3478

EpiCase AF: 0.865

EpiControl AF: 0.865

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 1 Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.0
DANN	Benign	0.62
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

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Other links and lift over

dbSNP: rs2229463; hg19: chr14-24718515; COSMIC: COSV104392346; COSMIC: COSV104392346;