19-40014598-G-A

Variant summary

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

The NM_178544.5(ZNF546):c.1328G>A(p.Cys443Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF546 NM_178544.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63

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 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	c.1328G>A	p.Cys443Tyr	missense_variant	7/7	ENST00000347077.9
ZNF546	NM_001297763.2	c.1250G>A	p.Cys417Tyr	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF546	ENST00000347077.9	c.1328G>A	p.Cys443Tyr	missense_variant	7/7	1	NM_178544.5	P2
ZNF546	ENST00000600094.5	c.1250G>A	p.Cys417Tyr	missense_variant	7/7	2		A2
ZNF546	ENST00000596894.5	c.77-1830G>A		intron_variant		3
ZNF546	ENST00000651981.1	c.*1282G>A		3_prime_UTR_variant, NMD_transcript_variant	8/8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461312 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726956

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Jan 19, 2024

The c.1328G>A (p.C443Y) 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 1328, causing the cysteine (C) at amino acid position 443 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	0.81
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	0.91	D
PrimateAI	Uncertain	0.66	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.51
MutPred		0.69		.;Gain of phosphorylation at C443 (P = 0.0643);
MVP		0.95
MPC		0.55
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.90
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-40520505;