19-40007329-G-T

Position:

• chr19-40007329-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178544.5(ZNF546):​c.227G>T​(p.Cys76Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF546 NM_178544.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.380

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084399074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF546	NM_178544.5	c.227G>T	p.Cys76Phe	missense_variant	5/7	ENST00000347077.9	NP_848639.2
ZNF546	NM_001297763.2	c.149G>T	p.Cys50Phe	missense_variant	5/7		NP_001284692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF546	ENST00000347077.9	c.227G>T	p.Cys76Phe	missense_variant	5/7	1	NM_178544.5	ENSP00000339823.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Sep 29, 2023

The c.227G>T (p.C76F) alteration is located in exon 5 (coding exon 3) of the ZNF546 gene. This alteration results from a G to T substitution at nucleotide position 227, causing the cysteine (C) at amino acid position 76 to be replaced by a phenylalanine (F). 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	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.75
DEOGEN2	Benign	0.013	.;.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.084	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	.;.;.;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	.;.;.;D;.
REVEL	Benign	0.071
Sift	Benign	0.70	.;.;.;T;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.031	.;.;.;B;.
Vest4		0.28, 0.28
MutPred		0.53		.;.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.51
MPC		0.37
ClinPred		0.091	T
GERP RS		-0.51
Varity_R		0.095
gMVP		0.035

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-40513236; COSMIC: COSV61258052;