Genetic Variant NM_007113.4:c.991C>T (chr1-152112226-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPP5_Moderate

The NM_007113.4(TCHH):c.991C>T(p.Gln331*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,565,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 24)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

TCHH
NM_007113.4 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

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_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.83 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PP5

Variant 1-152112226-G-A is Pathogenic according to our data. Variant chr1-152112226-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374835.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007113.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCHH	NM_007113.4	MANE Select	c.991C>T	p.Gln331*	stop_gained	Exon 3 of 3	NP_009044.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCHH	ENST00000614923.2	TSL:5 MANE Select	c.991C>T	p.Gln331*	stop_gained	Exon 3 of 3	ENSP00000480484.1

Frequencies

GnomAD3 genomes

AF:

0.000530

AC:

AN:

120818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000703

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000131

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000858

Gnomad OTH

AF:

0.000613

GnomAD2 exomes

AF:

0.000327

AC:

AN:

238272

AF XY:

0.000299

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000224

Gnomad NFE exome

AF:

0.000517

Gnomad OTH exome

AF:

0.000858

GnomAD4 exome

AF:

0.000367

AC:

530

AN:

1444114

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

264

AN XY:

718574

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33212

American (AMR)

AF:

0.000423

AC:

AN:

42580

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25790

East Asian (EAS)

AF:

0.00

AC:

AN:

37934

South Asian (SAS)

AF:

0.00

AC:

AN:

85482

European-Finnish (FIN)

AF:

0.000107

AC:

AN:

46724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.000440

AC:

487

AN:

1107100

Other (OTH)

AF:

0.000336

AC:

AN:

59568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000529

AC:

AN:

120908

Hom.:

Cov.:

AF XY:

0.000545

AC XY:

AN XY:

58734

show subpopulations

African (AFR)

AF:

0.000154

AC:

AN:

32396

American (AMR)

AF:

0.000703

AC:

AN:

11376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3018

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00

AC:

AN:

3336

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

7606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

156

European-Non Finnish (NFE)

AF:

0.000858

AC:

AN:

57090

Other (OTH)

AF:

0.000609

AC:

AN:

1642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

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:

0.000274

Hom.:

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.000600

AC:

ExAC

AF:

0.000356

AC:

EpiCase

AF:

0.000656

EpiControl

AF:

0.000358

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Uncombable hair syndrome 3 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.032

PhyloP100

0.53

Vest4

0.10

GERP RS

-0.013

Mutation Taster

=77/123

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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