12-109903941-C-G

Variant names:

• chr12-109903941-C-G
• rs762610842
• NM_001143852.2:c.193C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001143852.2(TCHP):​c.193C>G​(p.His65Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,764 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. H65L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TCHP NM_001143852.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.163
• Publications: 0 publications found

Genes affected

TCHP (HGNC:28135): (trichoplein keratin filament binding) Involved in apoptotic process; negative regulation of cell growth; and negative regulation of cilium assembly. Located in several cellular components, including apical cortex; cytoskeleton; and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042829543).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143852.2. 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
	TCHP	NM_001143852.2	MANE Select	c.193C>G	p.His65Asp	missense	Exon 3 of 13	NP_001137324.1	Q9BT92
	TCHP	NM_032300.5		c.193C>G	p.His65Asp	missense	Exon 3 of 13	NP_115676.1	Q9BT92

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCHP	ENST00000405876.9	TSL:1 MANE Select	c.193C>G	p.His65Asp	missense	Exon 3 of 13	ENSP00000384520.4	Q9BT92
	TCHP	ENST00000312777.9	TSL:1	c.193C>G	p.His65Asp	missense	Exon 3 of 13	ENSP00000324404.5	Q9BT92
	TCHP	ENST00000536408.2	TSL:1	c.193C>G	p.His65Asp	missense	Exon 3 of 5	ENSP00000441835.2	F5GWH6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452764 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721758

African (AFR) AF: 0.00 AC: 0 AN: 33352

American (AMR) AF: 0.00 AC: 0 AN: 43600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 84472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4802

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108474

Other (OTH) AF: 0.00 AC: 0 AN: 59986

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.16
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.074
Sift	Benign	1.0	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.17		Gain of catalytic residue at Y60 (P = 0.0817)
MVP		0.23
MPC		0.093
ClinPred		0.076	T
GERP RS		0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.051
gMVP		0.22
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs762610842; hg19: chr12-110341746;