Variant 19-40014178-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_178544.5(ZNF546):c.908G>A(p.Cys303Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZNF546
NM_178544.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.16

Variant links:

Genes affected

ZNF546 (HGNC:28671): (zinc finger protein 546) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be integral component of membrane. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF546 links:

Genome browser will be placed here

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	UniProt
ZNF546	NM_178544.5 linkuse as main transcript	c.908G>A	p.Cys303Tyr	missense_variant	7/7	ENST00000347077.9
ZNF546	NM_001297763.2 linkuse as main transcript	c.830G>A	p.Cys277Tyr	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ZNF546	ENST00000347077.9 linkuse as main transcript	c.908G>A	p.Cys303Tyr	missense_variant	7/7	1	NM_178544.5	P2
ZNF546	ENST00000600094.5 linkuse as main transcript	c.830G>A	p.Cys277Tyr	missense_variant	7/7	2		A2
ZNF546	ENST00000596894.5 linkuse as main transcript	c.77-2250G>A		intron_variant		3
ZNF546	ENST00000651981.1 linkuse as main transcript	c.*862G>A		3_prime_UTR_variant, NMD_transcript_variant	8/8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.00000398

AC:

AN:

251382

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.00000205

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

Dec 12, 2023

The c.908G>A (p.C303Y) alteration is located in exon 7 (coding exon 5) of the ZNF546 gene. This alteration results from a G to A substitution at nucleotide position 908, causing the cysteine (C) at amino acid position 303 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

0.69

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Uncertain

-0.040

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.85

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Pathogenic

0.86

MutationTaster

Benign

0.95

PrimateAI

Uncertain

0.66

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

.;D

Vest4

0.23

MutPred

0.80

.;Loss of methylation at K304 (P = 0.0279);

MVP

0.96

MPC

0.51

ClinPred

1.0

GERP RS

2.7

Varity_R

0.67

gMVP

0.16

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