Genetic Variant NM_000359.3:c.944G>T (chr14-24259744-C-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3PM1PM5PP2PP3PP5_Very_Strong

The NM_000359.3(TGM1):c.944G>T(p.Arg315Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,611,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000914639: Testing in NHEK cells found that the p.Arg315Leu variant demonstrated increased protein stability, increased half-life and prevented proteolytic processing into the active form of the enzyme (Candi et al. 1998)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R315P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TGM1
NM_000359.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.56

Publications

19 publications found

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]

TGM1 Gene-Disease associations (from GenCC):

autosomal recessive congenital ichthyosis 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, G2P
acral self-healing collodion baby
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
bathing suit ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital non-bullous ichthyosiform erythroderma
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
lamellar ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
self-healing collodion baby
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TGM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000914639: Testing in NHEK cells found that the p.Arg315Leu variant demonstrated increased protein stability, increased half-life and prevented proteolytic processing into the active form of the enzyme (Candi et al. 1998).; SCV000490850: Published functional studies demonstrate a damaging effect with impaired proteolytic processing, reduced activity of membrane-bound transglutaminase 1 in keratinocytes, and enhanced stability of the mutant protein; variant described using alternate nomenclature as R314L (Candi et al., 1998; Trindade et al., 2010); PMID: 31168818, 28403434, 19863506, 20522418, 10232404, 31589614, 35698621, 16977323, 9593710; SCV001217237: Experimental studies have shown that this missense change affects TGM1 function (PMID: 9593710).

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000359.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-24259744-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2034409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 81 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Gene score misZ: -0.060191 (below the threshold of 3.09). Trascript score misZ: 1.7514 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive congenital ichthyosis 1, lamellar ichthyosis, congenital non-bullous ichthyosiform erythroderma, self-healing collodion baby, bathing suit ichthyosis, acral self-healing collodion baby.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.787

PP5

Variant 14-24259744-C-A is Pathogenic according to our data. Variant chr14-24259744-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000359.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM1	NM_000359.3	MANE Select	c.944G>T	p.Arg315Leu	missense	Exon 6 of 15	NP_000350.1	P22735-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TGM1	ENST00000206765.11	TSL:1 MANE Select	c.944G>T	p.Arg315Leu	missense	Exon 6 of 15	ENSP00000206765.6	P22735-1
TGM1	ENST00000879556.1		c.944G>T	p.Arg315Leu	missense	Exon 5 of 14	ENSP00000549615.1
TGM1	ENST00000559136.1	TSL:5	c.17G>T	p.Arg6Leu	missense	Exon 2 of 7	ENSP00000453337.1	H0YLT9

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000406

AC:

AN:

246144

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.000572

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1459718

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726038

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52604

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111344

Other (OTH)

AF:

0.0000332

AC:

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000191

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.000628

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive congenital ichthyosis 1 (9)

not provided (2)

TGM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.85

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.79

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.9

PhyloP100

7.6

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.84

Sift

Uncertain

0.020

Sift4G

Uncertain

0.059

Polyphen

0.99

Vest4

0.97

MVP

0.98

MPC

1.0

ClinPred

0.83

GERP RS

4.9

PromoterAI

0.017

Neutral

(source)

Varity_R

0.62

gMVP

0.85

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over