Genetic Variant NM_007113.4:c.991C>G (chr1-152112226-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_007113.4(TCHH):c.991C>G(p.Gln331Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.000017 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TCHH
NM_007113.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.534

Publications

8 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037324637).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCHH	NM_007113.4 link	c.991C>G	p.Gln331Glu	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.991C>G	p.Gln331Glu	missense_variant	Exon 3 of 3	5	NM_007113.4	ENSP00000480484.1		Q07283

Frequencies

GnomAD3 genomes

AF:

0.0000166

AC:

AN:

120818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000619

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000420

AC:

AN:

238272

AF XY:

0.0000537

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000917

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000831

AC:

AN:

1444114

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

718584

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33212

American (AMR)

AF:

0.0000235

AC:

AN:

42576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25790

East Asian (EAS)

AF:

0.00

AC:

AN:

37928

South Asian (SAS)

AF:

0.000117

AC:

AN:

85482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107112

Other (OTH)

AF:

0.0000168

AC:

AN:

59566

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000166

AC:

AN:

120818

Hom.:

Cov.:

AF XY:

0.0000341

AC XY:

AN XY:

58638

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000619

AC:

AN:

32290

American (AMR)

AF:

0.00

AC:

AN:

11372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3018

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.00

AC:

AN:

3346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

166

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57092

Other (OTH)

AF:

0.00

AC:

AN:

1632

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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:

0.00

Hom.:

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00156

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.63

CADD

Benign

8.5

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0029

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0033

LIST_S2

Uncertain

0.90

.;D

M_CAP

Benign

0.0038

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.53

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.027

Sift

Pathogenic

0.0

D;.

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.22

MutPred

0.32

Loss of MoRF binding (P = 0.0811);Loss of MoRF binding (P = 0.0811);

MVP

0.32

MPC

0.29

ClinPred

0.027

GERP RS

-0.013

Varity_R

0.13

gMVP

0.43

Mutation Taster

=94/6

polymorphism

(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