chr1-152107612-C-T

Position:

• chr1-152107612-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007113.4(TCHH):​c.5605G>A​(p.Glu1869Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: TCHH NM_007113.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09606323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCHH	NM_007113.4	c.5605G>A	p.Glu1869Lys	missense_variant	3/3	ENST00000614923.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCHH	ENST00000614923.2	c.5605G>A	p.Glu1869Lys	missense_variant	3/3	5	NM_007113.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461844 Hom.: 0 Cov.: 110 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.5605G>A (p.E1869K) alteration is located in exon 2 (coding exon 2) of the TCHH gene. This alteration results from a G to A substitution at nucleotide position 5605, causing the glutamic acid (E) at amino acid position 1869 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0013	T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.56	.;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.75	N;.
REVEL	Benign	0.025
Sift	Uncertain	0.016	D;.
Sift4G	Benign	0.31	T;T
Polyphen		0.28	B;B
Vest4		0.21
MutPred		0.40		Gain of MoRF binding (P = 8e-04);Gain of MoRF binding (P = 8e-04);
MVP		0.48
MPC		0.46
ClinPred		0.15	T
GERP RS		1.6
Varity_R		0.13
gMVP		0.036

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

LitVar

Other links and lift over

dbSNP: rs1658143013; hg19: chr1-152080088;