Genetic Variant ZNF557:p.Tyr208Cys (chr19-7083074-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024341.3(ZNF557):c.623A>G(p.Tyr208Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZNF557
NM_024341.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.143

Publications

0 publications found

Variant links:

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]

ZNF557 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27709556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF557	NM_024341.3 link	c.623A>G	p.Tyr208Cys	missense_variant	Exon 8 of 8	ENST00000252840.11	NP_077317.2	Q8N988-2
ZNF557	NM_001044387.2 link	c.623A>G	p.Tyr208Cys	missense_variant	Exon 8 of 8		NP_001037852.1	Q8N988-2
ZNF557	NM_001044388.2 link	c.602A>G	p.Tyr201Cys	missense_variant	Exon 8 of 8		NP_001037853.1	Q8N988-1
ZNF557	XM_047439432.1 link	c.602A>G	p.Tyr201Cys	missense_variant	Exon 8 of 8		XP_047295388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF557	ENST00000252840.11 link	c.623A>G	p.Tyr208Cys	missense_variant	Exon 8 of 8	1	NM_024341.3	ENSP00000252840.5		Q8N988-2
ZNF557	ENST00000414706.2 link	c.602A>G	p.Tyr201Cys	missense_variant	Exon 8 of 8	2		ENSP00000404065.2		Q8N988-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250380

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727202

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111954

Other (OTH)

AF:

0.00

AC:

AN:

60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.623A>G (p.Y208C) alteration is located in exon 8 (coding exon 6) of the ZNF557 gene. This alteration results from a A to G substitution at nucleotide position 623, causing the tyrosine (Y) at amino acid position 208 to be replaced by a cysteine (C). 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

0.71

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.24

.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.0

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

.;L

PhyloP100

-0.14

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-7.0

D;.

REVEL

Benign

0.036

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;D

Vest4

0.23

MutPred

0.61

.;Loss of phosphorylation at Y201 (P = 0.0248);

MVP

0.49

MPC

0.44

ClinPred

0.66

GERP RS

-1.1

Varity_R

0.26

gMVP

0.10

Mutation Taster

=94/6

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over