19-2852465-A-G

Position:

• chr19-2852465-A-G

Variant summary

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

The NM_152791.5(ZNF555):​c.400A>G​(p.Lys134Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,224 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ZNF555 NM_152791.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0180

Genes affected

ZNF555 (HGNC:28382): (zinc finger protein 555) 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]

ENSG00000267063 (HGNC:):

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=0.06370145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF555	NM_152791.5	c.400A>G	p.Lys134Glu	missense_variant	4/4	ENST00000334241.9	NP_690004.4
ZNF555	NM_001172775.2	c.397A>G	p.Lys133Glu	missense_variant	4/4		NP_001166246.1
ZNF555	XM_011527716.3	c.406A>G	p.Lys136Glu	missense_variant	4/4		XP_011526018.1
ZNF555	XM_017026375.2	c.403A>G	p.Lys135Glu	missense_variant	4/4		XP_016881864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF555	ENST00000334241.9	c.400A>G	p.Lys134Glu	missense_variant	4/4	1	NM_152791.5	ENSP00000334853.3
ZNF555	ENST00000591539.1	c.397A>G	p.Lys133Glu	missense_variant	4/4	2		ENSP00000467893.1
ZNF555	ENST00000585966.5	c.304A>G	p.Lys102Glu	missense_variant	4/4	4		ENSP00000466982.1
ENSG00000267063	ENST00000589365.1	n.398-5081T>C		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

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

Aug 26, 2022

The c.400A>G (p.K134E) alteration is located in exon 4 (coding exon 4) of the ZNF555 gene. This alteration results from a A to G substitution at nucleotide position 400, causing the lysine (K) at amino acid position 134 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	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.8
DANN	Benign	0.64
DEOGEN2	Benign	0.074	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00099	N
LIST_S2	Benign	0.036	T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.26	N;.;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.1	N;.;.
REVEL	Benign	0.014
Sift	Benign	0.14	T;.;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.089
MutPred		0.46		Loss of methylation at K134 (P = 0.0115);.;.;
MVP		0.18
MPC		0.052
ClinPred		0.038	T
GERP RS		-1.6
Varity_R		0.089
gMVP		0.043

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: rs1486097402; hg19: chr19-2852463;