Genetic Variant TCHH:p.Leu790Met (chr1-152110849-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_007113.4(TCHH):c.2368T>A(p.Leu790Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,608,706 control chromosomes in the GnomAD database, including 26,853 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 2128 hom., cov: 32)

Exomes 𝑓: 0.17 ( 24725 hom. )

Consequence

TCHH
NM_007113.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00600

Publications

47 publications found

Variant links:

Genes affected

TCHH (HGNC:11791): (trichohyalin) The protein encoded by this gene forms crosslinked complexes with itself and keratin intermediate filaments to provide mechanical strength to the hair follicle inner root sheath. The encoded protein also is important for structural integrity of the filiform papillae of the tongue. Defects in this gene are a cause of uncombable hair syndrome. [provided by RefSeq, Feb 2017]

TCHH Gene-Disease associations (from GenCC):

uncombable hair syndrome 3
Inheritance: AR Classification: LIMITED Submitted by: G2P

TCHH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053429008).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCHH	NM_007113.4 link	c.2368T>A	p.Leu790Met	missense_variant	Exon 3 of 3	ENST00000614923.2	NP_009044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCHH	ENST00000614923.2 link	c.2368T>A	p.Leu790Met	missense_variant	Exon 3 of 3	5	NM_007113.4	ENSP00000480484.1

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21279

AN:

150848

Hom.:

2126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0339

Gnomad AMI

AF:

0.0887

Gnomad AMR

AF:

0.111

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.00180

Gnomad SAS

AF:

0.0857

Gnomad FIN

AF:

0.286

Gnomad MID

AF:

0.148

Gnomad NFE

AF:

0.206

Gnomad OTH

AF:

0.147

GnomAD2 exomes

AF:

0.152

AC:

37102

AN:

244738

AF XY:

0.155

show subpopulations

Gnomad AFR exome

AF:

0.0266

Gnomad AMR exome

AF:

0.0866

Gnomad ASJ exome

AF:

0.115

Gnomad EAS exome

AF:

0.000557

Gnomad FIN exome

AF:

0.286

Gnomad NFE exome

AF:

0.207

Gnomad OTH exome

AF:

0.169

GnomAD4 exome

AF:

0.174

AC:

254098

AN:

1457738

Hom.:

24725

Cov.:

114

AF XY:

0.174

AC XY:

125990

AN XY:

725418

show subpopulations

African (AFR)

AF:

0.0279

AC:

934

AN:

33474

American (AMR)

AF:

0.0877

AC:

3920

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.114

AC:

2988

AN:

26112

East Asian (EAS)

AF:

0.000529

AC:

AN:

39698

South Asian (SAS)

AF:

0.0998

AC:

8609

AN:

86240

European-Finnish (FIN)

AF:

0.288

AC:

14236

AN:

49514

Middle Eastern (MID)

AF:

0.174

AC:

1006

AN:

5768

European-Non Finnish (NFE)

AF:

0.192

AC:

213007

AN:

1111868

Other (OTH)

AF:

0.155

AC:

9377

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

14651

29301

43952

58602

73253

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6950

13900

20850

27800

34750

<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:

0.141

AC:

21273

AN:

150968

Hom.:

2128

Cov.:

AF XY:

0.142

AC XY:

10480

AN XY:

73788

show subpopulations

African (AFR)

AF:

0.0338

AC:

1385

AN:

41000

American (AMR)

AF:

0.111

AC:

1683

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

409

AN:

3452

East Asian (EAS)

AF:

0.00181

AC:

AN:

4984

South Asian (SAS)

AF:

0.0861

AC:

413

AN:

4794

European-Finnish (FIN)

AF:

0.286

AC:

2997

AN:

10494

Middle Eastern (MID)

AF:

0.138

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.206

AC:

13954

AN:

67750

Other (OTH)

AF:

0.145

AC:

303

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

882

1764

2647

3529

4411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

226

452

678

904

1130

<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:

0.161

Hom.:

831

Bravo

AF:

0.119

TwinsUK

AF:

0.191

AC:

709

ALSPAC

AF:

0.190

AC:

734

ESP6500AA

AF:

0.0360

AC:

145

ESP6500EA

AF:

0.178

AC:

1494

ExAC

AF:

0.155

AC:

18711

Asia WGS

AF:

0.0420

AC:

148

AN:

3478

EpiCase

AF:

0.189

EpiControl

AF:

0.186

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.0024

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.20

.;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.81

L;L

PhyloP100

0.0060

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.32

N;.

REVEL

Benign

0.032

Sift

Pathogenic

0.0

D;.

Sift4G

Benign

0.23

T;T

Polyphen

0.99

D;D

Vest4

0.052

MPC

0.26

ClinPred

0.0082

GERP RS

-0.58

Varity_R

0.10

gMVP

0.013

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over