chr19-9324706-C-T

Variant names:

• chr19-9324706-C-T
• rs1363222776
• NM_032497.3:c.-194C>T

Variant summary

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

The NM_032497.3(ZNF559):​c.-194C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000522 in 1,532,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: ZNF559 NM_032497.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.943
• 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=0.07552603).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032497.3. 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
	ZNF559	NM_032497.3	MANE Select	c.-194C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	NP_115886.1	Q9BR84-1
	ZNF559	NM_032497.3	MANE Select	c.-194C>T		5_prime_UTR	Exon 2 of 7	NP_115886.1	Q9BR84-1
	ZNF559	NM_001202407.3		c.-267C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001189336.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF559	ENST00000603380.6	TSL:2 MANE Select	c.-194C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000474760.1	Q9BR84-1
	ZNF559-ZNF177	ENST00000541595.6	TSL:2	c.-554C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	ENSP00000445323.1
	ZNF559	ENST00000586255.5	TSL:1	c.-269C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000465787.2	K7EKU6

Frequencies

GnomAD3 genomes AF: 0.00000663 AC: 1 AN: 150912 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000223 AC: 3 AN: 134612 AF XY: 0.0000273

Gnomad AFR exome AF: 0.000155

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: 0.0000378

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000507 AC: 7 AN: 1381642 Hom.: 0 Cov.: 33 AF XY: 0.00000440 AC XY: 3 AN XY: 681804

African (AFR) AF: 0.0000638 AC: 2 AN: 31334

American (AMR) AF: 0.00 AC: 0 AN: 35598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25076

East Asian (EAS) AF: 0.00 AC: 0 AN: 35620

South Asian (SAS) AF: 0.00 AC: 0 AN: 79196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1077702

Other (OTH) AF: 0.00 AC: 0 AN: 57708

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150912 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73644

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

African (AFR) AF: 0.0000245 AC: 1 AN: 40828

American (AMR) AF: 0.00 AC: 0 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67858

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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	0.24
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.5
DANN	Benign	0.62
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.00091	T
MetaRNN	Benign	0.076	T
PhyloP100		-0.94
PrimateAI	Benign	0.43	T
Sift4G	Uncertain	0.012	D
Vest4		0.22
MVP		0.20
GERP RS		-0.20
PromoterAI		0.026	Neutral
gMVP		0.53
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1363222776; hg19: chr19-9435382;