19-40014951-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.1681G>T(p.Ala561Ser) 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: -0.770

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=0.094029784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF546	NM_178544.5	c.1681G>T	p.Ala561Ser	missense_variant	7/7	ENST00000347077.9
ZNF546	NM_001297763.2	c.1603G>T	p.Ala535Ser	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF546	ENST00000347077.9	c.1681G>T	p.Ala561Ser	missense_variant	7/7	1	NM_178544.5	P2
ZNF546	ENST00000600094.5	c.1603G>T	p.Ala535Ser	missense_variant	7/7	2		A2
ZNF546	ENST00000596894.5	c.77-1477G>T		intron_variant		3
ZNF546	ENST00000651981.1	c.*1635G>T		3_prime_UTR_variant, NMD_transcript_variant	8/8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

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

Mar 01, 2024

The c.1681G>T (p.A561S) alteration is located in exon 7 (coding exon 5) of the ZNF546 gene. This alteration results from a G to T substitution at nucleotide position 1681, causing the alanine (A) at amino acid position 561 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	7.7
Dann	Uncertain	0.99
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.079	N
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.12	T;T
Polyphen		0.0010	.;B
Vest4		0.056
MutPred		0.54		.;Gain of disorder (P = 0.0108);
MVP		0.21
MPC		0.30
ClinPred		0.11	T
GERP RS		-1.9
Varity_R		0.062
gMVP		0.0089

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-40520858;