19-40014061-A-T

Position:

• chr19-40014061-A-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.791A>T​(p.His264Leu) 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. 15/21 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: 0.991

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=0.10433555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF546	NM_178544.5	c.791A>T	p.His264Leu	missense_variant	7/7	ENST00000347077.9	NP_848639.2
ZNF546	NM_001297763.2	c.713A>T	p.His238Leu	missense_variant	7/7		NP_001284692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF546	ENST00000347077.9	c.791A>T	p.His264Leu	missense_variant	7/7	1	NM_178544.5	ENSP00000339823.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Mar 31, 2023

The c.791A>T (p.H264L) alteration is located in exon 7 (coding exon 5) of the ZNF546 gene. This alteration results from a A to T substitution at nucleotide position 791, causing the histidine (H) at amino acid position 264 to be replaced by a leucine (L). 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	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.027	.;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.34	N
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.92	.;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	.;N
REVEL	Benign	0.079
Sift	Benign	0.074	.;T
Sift4G	Uncertain	0.018	D;D
Polyphen		0.0	.;B
Vest4		0.16
MutPred		0.46		.;Loss of disorder (P = 0.0619);
MVP		0.32
MPC		0.10
ClinPred		0.11	T
GERP RS		2.5
Varity_R		0.085
gMVP		0.047

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: rs751530701; hg19: chr19-40519968;