Variant 19-36877656-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001242472.2(ZNF345):c.826C>T(p.His276Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,862 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: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ZNF345
NM_001242472.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08

Variant links:

Genes affected

ZNF345 (HGNC:16367): (zinc finger protein 345) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF345 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF345	NM_001242472.2 linkuse as main transcript	c.826C>T	p.His276Tyr	missense_variant	3/3	ENST00000420450.6	NP_001229401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF345	ENST00000420450.6 linkuse as main transcript	c.826C>T	p.His276Tyr	missense_variant	3/3	1	NM_001242472.2	ENSP00000431216	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251130

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00000274

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

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 05, 2023

The c.826C>T (p.H276Y) alteration is located in exon 3 (coding exon 1) of the ZNF345 gene. This alteration results from a C to T substitution at nucleotide position 826, causing the histidine (H) at amino acid position 276 to be replaced by a tyrosine (Y). 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

0.96

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T;T;T;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.95

.;.;.;.;D;D

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

3.8

H;H;H;H;H;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.9

.;.;D;D;.;.

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

.;.;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;.

Polyphen

0.056

B;B;B;B;B;.

Vest4

0.60

MutPred

0.79

Loss of disorder (P = 0.0621);Loss of disorder (P = 0.0621);Loss of disorder (P = 0.0621);Loss of disorder (P = 0.0621);Loss of disorder (P = 0.0621);.;

MVP

0.70

MPC

0.69

ClinPred

0.97

GERP RS

2.9

Varity_R

0.61

gMVP

0.21

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