chr12-109908697-G-T

Variant names:

• chr12-109908697-G-T
• rs923890718
• NM_001143852.2:c.811G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001143852.2(TCHP):​c.811G>T​(p.Gly271Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000695 in 1,439,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TCHP NM_001143852.2 missense, splice_region
• Scores: Splicing: ADA: 0.9904
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.37

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCHP	NM_001143852.2	c.811G>T	p.Gly271Trp	missense_variant, splice_region_variant	Exon 7 of 13	ENST00000405876.9	NP_001137324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCHP	ENST00000405876.9	c.811G>T	p.Gly271Trp	missense_variant, splice_region_variant	Exon 7 of 13	1	NM_001143852.2	ENSP00000384520.4
TCHP	ENST00000312777.9	c.811G>T	p.Gly271Trp	missense_variant, splice_region_variant	Exon 7 of 13	1		ENSP00000324404.5
TCHP	ENST00000544838.5	n.811G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 15	2		ENSP00000440838.1
TCHP	ENST00000549550.1	n.-118G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439724 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 713736

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: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.027	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.29		Loss of loop (P = 0.1258);Loss of loop (P = 0.1258);
MVP		0.43
MPC		0.44
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.18		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: rs923890718; hg19: chr12-110346502;