NM_007113.4:c.991C>G

Variant names:

• chr1-152112226-G-C
• rs201930497
• NM_007113.4:c.991C>G

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.534
• Publications: 8 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037324637).

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>G	p.Gln331Glu	missense	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>G	p.Gln331Glu	missense	Exon 3 of 3	ENSP00000480484.1

Frequencies

GnomAD3 genomes AF: 0.0000166 AC: 2 AN: 120818 Hom.: 0 Cov.: 24

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: 10 AN: 238272 AF XY: 0.0000537

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: 12 AN: 1444114 Hom.: 0 Cov.: 69 AF XY: 0.0000111 AC XY: 8 AN XY: 718584

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

African (AFR) AF: 0.00 AC: 0 AN: 33212

American (AMR) AF: 0.0000235 AC: 1 AN: 42576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25790

East Asian (EAS) AF: 0.00 AC: 0 AN: 37928

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107112

Other (OTH) AF: 0.0000168 AC: 1 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.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000166 AC: 2 AN: 120818 Hom.: 0 Cov.: 24 AF XY: 0.0000341 AC XY: 2 AN XY: 58638

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

African (AFR) AF: 0.0000619 AC: 2 AN: 32290

American (AMR) AF: 0.00 AC: 0 AN: 11372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3018

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 3346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 166

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57092

Other (OTH) AF: 0.00 AC: 0 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.

Alfa AF: 0.00 Hom.: 0

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.5
DANN	Benign	0.79
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.53
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.027
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.22
MutPred		0.32		Loss of MoRF binding (P = 0.0811)
MVP		0.32
MPC		0.29
ClinPred		0.027	T
GERP RS		-0.013
Varity_R		0.13
gMVP		0.43
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs201930497; hg19: chr1-152084702; COSMIC: COSV64274337;