chr12-109903045-C-T

Variant names:

• chr12-109903045-C-T
• rs1869894048
• NM_001143852.2:c.19C>T

Variant summary

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

The NM_001143852.2(TCHP):​c.19C>T​(p.Pro7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 6.9e-7 (0 hom.)
• Consequence: TCHP NM_001143852.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.15

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

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=0.2176851).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCHP	NM_001143852.2	c.19C>T	p.Pro7Ser	missense_variant	Exon 2 of 13	ENST00000405876.9	NP_001137324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCHP	ENST00000405876.9	c.19C>T	p.Pro7Ser	missense_variant	Exon 2 of 13	1	NM_001143852.2	ENSP00000384520.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455986 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724560

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19C>T (p.P7S) alteration is located in exon 2 (coding exon 1) of the TCHP gene. This alteration results from a C to T substitution at nucleotide position 19, causing the proline (P) at amino acid position 7 to be replaced by a serine (S). 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	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D;T
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.0039
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.78	.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.12
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.63	P;P;.
Vest4		0.13
MutPred		0.32		Gain of catalytic residue at Y9 (P = 0.0025);Gain of catalytic residue at Y9 (P = 0.0025);Gain of catalytic residue at Y9 (P = 0.0025);
MVP		0.42
MPC		0.41
ClinPred		0.91	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.042

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1869894048; hg19: chr12-110340850;