Variant 7-149474902-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001394198.1(ZNF746):c.1465C>T(p.Arg489Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,384,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

ZNF746
NM_001394198.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31

Variant links:

Genes affected

ZNF746 (HGNC:21948): (zinc finger protein 746) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and ubiquitin protein ligase binding activity. Involved in negative regulation of transcription by RNA polymerase II; positive regulation of neuron death; and positive regulation of transcription by RNA polymerase II. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNF746 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF746	NM_001394198.1 linkuse as main transcript	c.1465C>T	p.Arg489Cys	missense_variant	7/7	ENST00000458143.7	NP_001381127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF746	ENST00000458143.7 linkuse as main transcript	c.1465C>T	p.Arg489Cys	missense_variant	7/7	2	NM_001394198.1	ENSP00000395007.3	A0A8J9FQ52
ZNF746	ENST00000340622.8 linkuse as main transcript	c.1417C>T	p.Arg473Cys	missense_variant	7/7	1		ENSP00000345140.3	Q6NUN9-1
ZNF746	ENST00000644635.1 linkuse as main transcript	c.1462C>T	p.Arg488Cys	missense_variant	7/7			ENSP00000493970.1	A0A2R8YDQ5
ZNF746	ENST00000685153.1 linkuse as main transcript	c.1420C>T	p.Arg474Cys	missense_variant	7/7			ENSP00000508891.1	Q6NUN9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000151

AC:

AN:

132428

Hom.:

AF XY:

0.0000138

AC XY:

AN XY:

72288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000194

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:

0.00000289

AC:

AN:

1384566

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000561

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000186

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

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

Apr 24, 2024

The c.1420C>T (p.R474C) alteration is located in exon 7 (coding exon 7) of the ZNF746 gene. This alteration results from a C to T substitution at nucleotide position 1420, causing the arginine (R) at amino acid position 474 to be replaced by a cysteine (C). 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

0.74

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Uncertain

0.46

T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.8

.;M;.

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-4.3

.;D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

.;D;D

Sift4G

Uncertain

0.0060

.;D;D

Polyphen

1.0, 1.0

.;D;D

Vest4

0.42, 0.42

MutPred

0.62

.;Loss of methylation at R473 (P = 0.0268);.;

MVP

0.79

MPC

1.8

ClinPred

0.97

GERP RS

3.8

Varity_R

0.37

gMVP

0.51

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