19-40015026-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178544.5(ZNF546):c.1756T>C(p.Cys586Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZNF546 NM_178544.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.919

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF546	NM_178544.5	c.1756T>C	p.Cys586Arg	missense_variant	7/7	ENST00000347077.9
ZNF546	NM_001297763.2	c.1678T>C	p.Cys560Arg	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF546	ENST00000347077.9	c.1756T>C	p.Cys586Arg	missense_variant	7/7	1	NM_178544.5	P2
ZNF546	ENST00000600094.5	c.1678T>C	p.Cys560Arg	missense_variant	7/7	2		A2
ZNF546	ENST00000596894.5	c.77-1402T>C		intron_variant		3
ZNF546	ENST00000651981.1	c.*1710T>C		3_prime_UTR_variant, NMD_transcript_variant	8/8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461840 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 22, 2023

The c.1756T>C (p.C586R) alteration is located in exon 7 (coding exon 5) of the ZNF546 gene. This alteration results from a T to C substitution at nucleotide position 1756, causing the cysteine (C) at amino acid position 586 to be replaced by an arginine (R). 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	0.93
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.69
MutPred		0.75		.;Gain of MoRF binding (P = 0.012);
MVP		0.75
MPC		0.39
ClinPred		1.0	D
GERP RS		1.9
Varity_R		0.84
gMVP		0.084

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: chr19-40520933;