19-57808978-A-C

Variant names:

• chr19-57808978-A-C
• NM_024762.3:c.286T>G

Variant summary

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

The NM_024762.3(ZNF552):​c.286T>G​(p.Cys96Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZNF552 NM_024762.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0600

Genes affected

ZNF552 (HGNC:26135): (zinc finger protein 552) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF586 (HGNC:25949): (zinc finger protein 586) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF552	NM_024762.3	c.286T>G	p.Cys96Gly	missense_variant	Exon 3 of 3	ENST00000391701.1	NP_079038.2
ZNF552	XM_005259267.5	c.274T>G	p.Cys92Gly	missense_variant	Exon 3 of 3		XP_005259324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF552	ENST00000391701.1	c.286T>G	p.Cys96Gly	missense_variant	Exon 3 of 3	2	NM_024762.3	ENSP00000375582.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.286T>G (p.C96G) alteration is located in exon 3 (coding exon 3) of the ZNF552 gene. This alteration results from a T to G substitution at nucleotide position 286, causing the cysteine (C) at amino acid position 96 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	Benign	0.34
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.84
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0029	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.060
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-11	D
REVEL	Benign	0.036
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.027	D
Polyphen		0.75	P
Vest4		0.14
MutPred		0.70		Gain of disorder (P = 0.0315);
MVP		0.69
MPC		1.2
ClinPred		0.54	D
GERP RS		0.86
Varity_R		0.28
gMVP		0.15
Mutation Taster		=88/12	polymorphism

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

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Other links and lift over

hg19: chr19-58320346;