19-40007329-G-T

Variant names:

• chr19-40007329-G-T
• rs1971616046
• NM_178544.5:c.227G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178544.5(ZNF546):​c.227G>T​(p.Cys76Phe) 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. 15/22 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: -0.380
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.084399074).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178544.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF546	NM_178544.5	MANE Select	c.227G>T	p.Cys76Phe	missense	Exon 5 of 7	NP_848639.2	Q86UE3
	ZNF546	NM_001297763.2		c.149G>T	p.Cys50Phe	missense	Exon 5 of 7	NP_001284692.1	M0QY24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF546	ENST00000347077.9	TSL:1 MANE Select	c.227G>T	p.Cys76Phe	missense	Exon 5 of 7	ENSP00000339823.3	Q86UE3
	ZNF546	ENST00000600094.5	TSL:2	c.149G>T	p.Cys50Phe	missense	Exon 5 of 7	ENSP00000469540.1	M0QY24
	ZNF546	ENST00000951738.1		c.149G>T	p.Cys50Phe	missense	Exon 5 of 7	ENSP00000621797.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.75
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.012	N
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.38
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.071
Sift	Benign	0.70	T
Sift4G	Benign	0.14	T
Polyphen		0.031	B
Vest4		0.28
MutPred		0.53		Loss of helix (P = 0.0558)
MVP		0.51
MPC		0.37
ClinPred		0.091	T
GERP RS		-0.51
Varity_R		0.095
gMVP		0.035
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1971616046; hg19: chr19-40513236; COSMIC: COSV61258052;