19-9339224-A-G

Position:

• chr19-9339224-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032497.3(ZNF559):​c.65A>G​(p.Asp22Gly) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF559 NM_032497.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38545334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF559	NM_032497.3	c.65A>G	p.Asp22Gly	missense_variant	5/7	ENST00000603380.6	NP_115886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF559	ENST00000603380.6	c.65A>G	p.Asp22Gly	missense_variant	5/7	2	NM_032497.3	ENSP00000474760.1
ZNF559-ZNF177	ENST00000541595.6	c.-391+642A>G		intron_variant		2		ENSP00000445323.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2023

The c.257A>G (p.D86G) alteration is located in exon 4 (coding exon 4) of the ZNF559 gene. This alteration results from a A to G substitution at nucleotide position 257, causing the aspartic acid (D) at amino acid position 86 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0091	.;T;.;.;.;.;.;.;T;.
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.039	T;T;T;.;T;T;T;T;.;T
M_CAP	Benign	0.00094	T
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;M;.;M;M;.;.;.;M;.
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.8	.;.;.;.;D;.;.;.;D;.
REVEL	Benign	0.095
Sift	Uncertain	0.015	.;.;.;.;D;.;.;.;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;.;.;.;.;.;D;.
Vest4		0.38
MutPred		0.66		.;Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;.;Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;
MVP		0.29
MPC		0.0089
ClinPred		0.81	D
GERP RS		1.4
Varity_R		0.38
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-9449900;