Genetic Variant NM_201631.4:c.326C>T (chr15-43260162-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_201631.4(TGM5):c.326C>T(p.Thr109Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 1,614,134 control chromosomes in the GnomAD database, including 178 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 19 hom., cov: 31)

Exomes 𝑓: 0.0060 ( 159 hom. )

Consequence

TGM5
NM_201631.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.540

Publications

12 publications found

Variant links:

Genes affected

TGM5 (HGNC:11781): (transglutaminase 5) This gene encodes a member of the transglutaminase family. The encoded protein catalyzes formation of protein cross-links between glutamine and lysine residues, often resulting in stabilization of protein assemblies. This reaction is calcium dependent. Mutations in this gene have been associated with acral peeling skin syndrome. [provided by RefSeq, Oct 2009]

TGM5 Gene-Disease associations (from GenCC):

acral peeling skin syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, PanelApp Australia

TGM5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0024375916).

BP6

Variant 15-43260162-G-A is Benign according to our data. Variant chr15-43260162-G-A is described in ClinVar as Benign. ClinVar VariationId is 137639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0788 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201631.4. 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
	TGM5	NM_201631.4	MANE Select	c.326C>T	p.Thr109Met	missense	Exon 3 of 13	NP_963925.2	O43548-1
	TGM5	NM_004245.4		c.190+238C>T		intron	N/A	NP_004236.1	O43548-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGM5	ENST00000220420.10	TSL:1 MANE Select	c.326C>T	p.Thr109Met	missense	Exon 3 of 13	ENSP00000220420.5	O43548-1
	TGM5	ENST00000349114.8	TSL:1	c.190+238C>T		intron	N/A	ENSP00000220419.8	O43548-2

Frequencies

GnomAD3 genomes

AF:

0.00624

AC:

950

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.0853

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00414

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00425

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00986

AC:

2476

AN:

251234

AF XY:

0.00939

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00552

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.0856

Gnomad FIN exome

AF:

0.00385

Gnomad NFE exome

AF:

0.00403

Gnomad OTH exome

AF:

0.00620

GnomAD4 exome

AF:

0.00600

AC:

8770

AN:

1461816

Hom.:

159

Cov.:

AF XY:

0.00589

AC XY:

4282

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33478

American (AMR)

AF:

0.00514

AC:

230

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00245

AC:

AN:

26136

East Asian (EAS)

AF:

0.0817

AC:

3242

AN:

39700

South Asian (SAS)

AF:

0.00268

AC:

231

AN:

86258

European-Finnish (FIN)

AF:

0.00328

AC:

175

AN:

53356

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00395

AC:

4392

AN:

1112012

Other (OTH)

AF:

0.00662

AC:

400

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

583

1165

1748

2330

2913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

206

412

618

824

1030

<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:

0.00624

AC:

950

AN:

152318

Hom.:

Cov.:

AF XY:

0.00659

AC XY:

491

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41588

American (AMR)

AF:

0.00562

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.0853

AC:

442

AN:

5180

South Asian (SAS)

AF:

0.00497

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00414

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00425

AC:

289

AN:

68010

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00649

Hom.:

Bravo

AF:

0.00604

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00977

AC:

1186

Asia WGS

AF:

0.0390

AC:

135

AN:

3478

EpiCase

AF:

0.00480

EpiControl

AF:

0.00326

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Acral peeling skin syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.48

CADD

Benign

2.5

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.029

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.23

PhyloP100

-0.54

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.5

REVEL

Benign

0.13

Sift

Benign

0.23

Sift4G

Benign

0.20

Polyphen

0.015

Vest4

0.15

MVP

0.27

MPC

0.16

ClinPred

0.0011

GERP RS

-5.0

Varity_R

0.033

gMVP

0.28

Mutation Taster

=95/5

polymorphism (auto)

(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