chr19-40013944-C-G

Variant names:

• chr19-40013944-C-G
• rs559263925
• NM_178544.5:c.674C>G

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.674C>G​(p.Ala225Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,668 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. A225V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF546 NM_178544.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.286
• 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=0.1153155).

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.674C>G	p.Ala225Gly	missense	Exon 7 of 7	NP_848639.2	Q86UE3
	ZNF546	NM_001297763.2		c.596C>G	p.Ala199Gly	missense	Exon 7 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.674C>G	p.Ala225Gly	missense	Exon 7 of 7	ENSP00000339823.3	Q86UE3
	ZNF546	ENST00000600094.5	TSL:2	c.596C>G	p.Ala199Gly	missense	Exon 7 of 7	ENSP00000469540.1	M0QY24
	ZNF546	ENST00000951738.1		c.596C>G	p.Ala199Gly	missense	Exon 7 of 7	ENSP00000621797.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249658 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459668 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725970

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.0000225 AC: 1 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110792

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.013	N
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.29
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.032
Sift	Benign	0.26	T
Sift4G	Uncertain	0.017	D
Polyphen		0.63	P
Vest4		0.098
MutPred		0.46		Gain of glycosylation at K224 (P = 0.1087)
MVP		0.31
MPC		0.18
ClinPred		0.25	T
GERP RS		1.9
Varity_R		0.10
gMVP		0.019
Mutation Taster		=99/1	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: rs559263925; hg19: chr19-40519851;