19-40007329-G-C

Variant names:

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

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>C​(p.Cys76Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C76F) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ZNF546 NM_178544.5 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.10307336).

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>C	p.Cys76Ser	missense	Exon 5 of 7	NP_848639.2	Q86UE3
	ZNF546	NM_001297763.2		c.149G>C	p.Cys50Ser	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>C	p.Cys76Ser	missense	Exon 5 of 7	ENSP00000339823.3	Q86UE3
	ZNF546	ENST00000600094.5	TSL:2	c.149G>C	p.Cys50Ser	missense	Exon 5 of 7	ENSP00000469540.1	M0QY24
	ZNF546	ENST00000951738.1		c.149G>C	p.Cys50Ser	missense	Exon 5 of 7	ENSP00000621797.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.4
DANN	Benign	0.59
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.035	N
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.38
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.092
Sift	Benign	0.40	T
Sift4G	Uncertain	0.021	D
Polyphen		0.059	B
Vest4		0.19
MutPred		0.56		Gain of disorder (P = 0.0011)
MVP		0.41
MPC		0.23
ClinPred		0.17	T
GERP RS		-0.51
Varity_R		0.082
gMVP		0.041
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1971616046; hg19: chr19-40513236;