19-9341884-G-A

Position:

• chr19-9341884-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032497.3(ZNF559):​c.433G>A​(p.Glu145Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF559 NM_032497.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.14

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021758407).
• BP6: Variant 19-9341884-G-A is Benign according to our data. Variant chr19-9341884-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3196701.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF559	NM_032497.3	c.433G>A	p.Glu145Lys	missense_variant	7/7	ENST00000603380.6	NP_115886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF559	ENST00000603380.6	c.433G>A	p.Glu145Lys	missense_variant	7/7	2	NM_032497.3	ENSP00000474760.1
ZNF559-ZNF177	ENST00000541595.6	c.-391+3302G>A		intron_variant		2		ENSP00000445323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.34
DANN	Benign	0.83
DEOGEN2	Benign	0.00079	.;T;.;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.000010	N
LIST_S2	Benign	0.48	T;T;T;T;.
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.022	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.7	.;N;.;.;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	2.4	.;.;.;.;N
REVEL	Benign	0.12
Sift	Benign	1.0	.;.;.;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0030	.;B;.;.;B
Vest4		0.099
MutPred		0.41		.;Gain of methylation at E145 (P = 0.0017);.;.;Gain of methylation at E145 (P = 0.0017);
MVP		0.28
MPC		0.0079
ClinPred		0.039	T
GERP RS		-1.3
Varity_R		0.024
gMVP		0.017

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

Publications

LitVar

Other links and lift over

dbSNP: rs1444668356; hg19: chr19-9452560;