19-31277331-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_020856.4(TSHZ3):c.2462C>T(p.Thr821Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,602 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T821A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: TSHZ3 NM_020856.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0897499).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHZ3	NM_020856.4	c.2462C>T	p.Thr821Met	missense_variant	2/2	ENST00000240587.5
TSHZ3	XM_047439132.1	c.2462C>T	p.Thr821Met	missense_variant	3/3
TSHZ3	NR_138035.2	n.258-49191C>T		intron_variant, non_coding_transcript_variant
TSHZ3	NR_138036.2	n.258-49191C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHZ3	ENST00000240587.5	c.2462C>T	p.Thr821Met	missense_variant	2/2	1	NM_020856.4	P1
TSHZ3	ENST00000651361.1	n.64-34456C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251302 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461392 Hom.: 0 Cov.: 30 AF XY: 0.0000509 AC XY: 37 AN XY: 726896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

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

Apr 25, 2022

The c.2462C>T (p.T821M) 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 2462, causing the threonine (T) at amino acid position 821 to be replaced by a methionine (M). 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	0.094
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.13
Sift	Benign	0.076	T
Sift4G	Uncertain	0.032	D
Polyphen		0.32	B
Vest4		0.42
MVP		0.21
MPC		0.38
ClinPred		0.19	T
GERP RS		4.3
Varity_R		0.041
gMVP		0.23

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: rs142735417; hg19: chr19-31768237; COSMIC: COSV99551942; COSMIC: COSV99551942;