19-7081410-A-G

Position:

• chr19-7081410-A-G

Variant summary

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

The NM_024341.3(ZNF557):​c.298A>G​(p.Lys100Glu) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF557 NM_024341.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.815

Genes affected

ZNF557 (HGNC:28632): (zinc finger protein 557) 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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030636698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF557	NM_024341.3	c.298A>G	p.Lys100Glu	missense_variant	6/8	ENST00000252840.11	NP_077317.2
ZNF557	NM_001044387.2	c.298A>G	p.Lys100Glu	missense_variant	6/8		NP_001037852.1
ZNF557	NM_001044388.2	c.277A>G	p.Lys93Glu	missense_variant	6/8		NP_001037853.1
ZNF557	XM_047439432.1	c.277A>G	p.Lys93Glu	missense_variant	6/8		XP_047295388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF557	ENST00000252840.11	c.298A>G	p.Lys100Glu	missense_variant	6/8	1	NM_024341.3	ENSP00000252840.5
ZNF557	ENST00000414706.2	c.277A>G	p.Lys93Glu	missense_variant	6/8	2		ENSP00000404065.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Sep 14, 2021

The c.298A>G (p.K100E) alteration is located in exon 6 (coding exon 4) of the ZNF557 gene. This alteration results from a A to G substitution at nucleotide position 298, causing the lysine (K) at amino acid position 100 to be replaced by a glutamic acid (E). 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	Benign	0.071
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.9
DANN	Benign	0.087
DEOGEN2	Benign	0.0058	.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00030	N
LIST_S2	Benign	0.015	T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.031	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.5	.;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.24	N;.
REVEL	Benign	0.017
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.094
MutPred		0.32		.;Loss of ubiquitination at K93 (P = 0.0141);
MVP		0.15
MPC		0.091
ClinPred		0.045	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.063
gMVP		0.056

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1977702066; hg19: chr19-7081421;