19-8812050-C-G

Variant names:

• chr19-8812050-C-G
• rs147518358
• NM_144693.3:c.440G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144693.3(ZNF558):​c.440G>C​(p.Arg147Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,433,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R147H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ZNF558 NM_144693.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.543
• Publications: 2 publications found

Genes affected

ZNF558 (HGNC:26422): (zinc finger protein 558) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060908526).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144693.3. 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
	ZNF558	NM_144693.3	MANE Select	c.440G>C	p.Arg147Pro	missense	Exon 10 of 10	NP_653294.1	Q96NG5-1
	ZNF558	NM_001304350.2		c.227G>C	p.Arg76Pro	missense	Exon 5 of 5	NP_001291279.1	Q96NG5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF558	ENST00000601372.6	TSL:2 MANE Select	c.440G>C	p.Arg147Pro	missense	Exon 10 of 10	ENSP00000471277.1	Q96NG5-1
	ZNF558	ENST00000301475.1	TSL:1	c.440G>C	p.Arg147Pro	missense	Exon 6 of 6	ENSP00000301475.1	Q96NG5-1
	ZNF558	ENST00000869419.1		c.440G>C	p.Arg147Pro	missense	Exon 10 of 10	ENSP00000539478.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000134 AC: 3 AN: 223472 AF XY: 0.0000166

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000972

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1433088 Hom.: 0 Cov.: 30 AF XY: 0.00000423 AC XY: 3 AN XY: 709786

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32536

American (AMR) AF: 0.00 AC: 0 AN: 40794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24238

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.0000246 AC: 2 AN: 81178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1097674

Other (OTH) AF: 0.00 AC: 0 AN: 59236

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00585934), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.00032	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.33	N
PhyloP100		0.54
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.038
Sift	Benign	0.33	T
Sift4G	Uncertain	0.038	D
Polyphen		0.52	P
Vest4		0.12
MutPred		0.37		Loss of MoRF binding (P = 0.0021)
MVP		0.27
MPC		0.31
ClinPred		0.059	T
GERP RS		-2.5
Varity_R		0.072
gMVP		0.25
Mutation Taster		=90/10	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: rs147518358; hg19: chr19-8922726;