19-9324215-C-G

Variant names:

• chr19-9324215-C-G
• rs946165663
• NM_032497.3:c.-219C>G

Variant summary

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

The NM_001202406.1(ZNF559):​c.37C>G​(p.Arg13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R13L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF559 NM_001202406.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.15
• Publications: 0 publications found

Genes affected

ZNF559 (HGNC:28197): (zinc finger protein 559) 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]

ZNF559-ZNF177 (HGNC:42964): (ZNF559-ZNF177 readthrough) This locus represents naturally occurring read-through transcription between the neighboring zinc finger protein 559 (ZNF559) and zinc finger protein 177 (ZNF177) genes on chromosome 19. Alternative splicing results in multiple transcript variants, which encode the ZNF177 protein due to either leaky scanning by ribosomes, or absence of the ZNF559 start codon. [provided by RefSeq, Jan 2011]

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=0.072835565).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001202406.1. 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
	ZNF559	NM_032497.3	MANE Select	c.-219C>G		5_prime_UTR	Exon 1 of 7	NP_115886.1	Q9BR84-1
	ZNF559	NM_001202406.1		c.37C>G	p.Arg13Gly	missense	Exon 1 of 6	NP_001189335.1	A0A0A0MTT2
	ZNF559	NM_001202408.1		c.37C>G	p.Arg13Gly	missense	Exon 1 of 6	NP_001189337.1	B4DP29

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF559	ENST00000603380.6	TSL:2 MANE Select	c.-219C>G		5_prime_UTR	Exon 1 of 7	ENSP00000474760.1	Q9BR84-1
	ZNF559	ENST00000586255.5	TSL:1	c.-294C>G		5_prime_UTR	Exon 1 of 7	ENSP00000465787.2	K7EKU6
	ZNF559	ENST00000592896.5	TSL:1	c.-294C>G		5_prime_UTR	Exon 1 of 7	ENSP00000466496.2	A0A0A0MTS4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383768 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 682842

⚠️ 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: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078852

Other (OTH) AF: 0.00 AC: 0 AN: 57896

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	0.31
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.4
DANN	Benign	0.59
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.00061	T
MetaRNN	Benign	0.073	T
PhyloP100		-2.1
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.071	T
Vest4		0.14
MVP		0.18
GERP RS		-1.6
PromoterAI		0.15	Neutral
gMVP		0.51
Mutation Taster		=297/3	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: rs946165663; hg19: chr19-9434891;