Variant 19-31276590-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_020856.4(TSHZ3):c.3203C>T(p.Pro1068Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,589,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

TSHZ3
NM_020856.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.57

Variant links:

Genes affected

TSHZ3 (HGNC:30700): (teashirt zinc finger homeobox 3) This gene encodes a zinc-finger transcription factor that regulates smooth muscle cell differentiation in the developing urinary tract. Consistent with this role, mice in which this gene has been inactivated exhibit abnormal gene expression in urinary tract smooth muscle cell precursors and kidney defects including hydronephrosis. The encoded transcription factor comprises a gene silencing complex that inhibits caspase expression. Reduced expression of this gene and consequent caspase upregulation may be correlated with progression of Alzheimer's disease in human patients. [provided by RefSeq, Jul 2016]

TSHZ3 links:

TSHZ3 (HGNC:):

TSHZ3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHZ3	NM_020856.4 linkuse as main transcript	c.3203C>T	p.Pro1068Leu	missense_variant	2/2	ENST00000240587.5	NP_065907.2	Q63HK5
TSHZ3	XM_047439132.1 linkuse as main transcript	c.3203C>T	p.Pro1068Leu	missense_variant	3/3		XP_047295088.1
TSHZ3	NR_138035.2 linkuse as main transcript	n.258-48450C>T		intron_variant
TSHZ3	NR_138036.2 linkuse as main transcript	n.258-48450C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHZ3	ENST00000240587.5 linkuse as main transcript	c.3203C>T	p.Pro1068Leu	missense_variant	2/2	1	NM_020856.4	ENSP00000240587.4		Q63HK5
TSHZ3	ENST00000651361.1 linkuse as main transcript	n.64-33715C>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00000415

AC:

AN:

240952

Hom.:

AF XY:

0.00

AC XY:

AN XY:

129808

show subpopulations

Gnomad AFR exome

AF:

0.0000621

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000278

AC:

AN:

1437368

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

711026

show subpopulations

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:

0.00000365

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2023

The c.3203C>T (p.P1068L) alteration is located in exon 2 (coding exon 2) of the TSHZ3 gene. This alteration results from a C to T substitution at nucleotide position 3203, causing the proline (P) at amino acid position 1068 to be replaced by a leucine (L). 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

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Benign

0.043

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.0

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.89

Vest4

0.90

MutPred

0.53

Loss of methylation at K1066 (P = 0.0533);

MVP

0.45

MPC

1.1

ClinPred

0.99

GERP RS

5.9

Varity_R

0.64

gMVP

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over