19-40014637-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_178544.5(ZNF546):c.1367T>C(p.Leu456Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 4.62

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF546	NM_178544.5	c.1367T>C	p.Leu456Pro	missense_variant	7/7	ENST00000347077.9
ZNF546	NM_001297763.2	c.1289T>C	p.Leu430Pro	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF546	ENST00000347077.9	c.1367T>C	p.Leu456Pro	missense_variant	7/7	1	NM_178544.5	P2
ZNF546	ENST00000600094.5	c.1289T>C	p.Leu430Pro	missense_variant	7/7	2		A2
ZNF546	ENST00000596894.5	c.77-1791T>C		intron_variant		3
ZNF546	ENST00000651981.1	c.*1321T>C		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

Apr 26, 2023

The c.1367T>C (p.L456P) 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 1367, causing the leucine (L) at amino acid position 456 to be replaced by a proline (P). 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	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.34	N
M_CAP	Benign	0.0058	T
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.55	T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.65
MutPred		0.80		.;Loss of stability (P = 0.031);
MVP		0.81
MPC		0.56
ClinPred		0.95	D
GERP RS		2.7
Varity_R		0.77
gMVP		0.31

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: chr19-40520544;