1-152107644-C-A

Variant names:

• chr1-152107644-C-A
• rs1658144406
• NM_007113.4:c.5573G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007113.4(TCHH):​c.5573G>T​(p.Arg1858Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1858P) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: TCHH NM_007113.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510
• Publications: 0 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: PanelApp Australia, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096523434).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCHH	NM_007113.4	MANE Select	c.5573G>T	p.Arg1858Leu	missense	Exon 3 of 3	NP_009044.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCHH	ENST00000614923.2	TSL:5 MANE Select	c.5573G>T	p.Arg1858Leu	missense	Exon 3 of 3	ENSP00000480484.1	Q07283

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome Cov.: 110

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.051
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.25	B
Vest4		0.38
MutPred		0.16		Loss of methylation at K1856 (P = 0.0449)
MVP		0.23
MPC		0.47
ClinPred		0.34	T
GERP RS		1.6
Varity_R		0.15
gMVP		0.023
Mutation Taster		=99/1	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: rs1658144406; hg19: chr1-152080120;