Variant 19-7081996-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024341.3(ZNF557):c.370G>A(p.Gly124Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,613,730 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 0.00059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 0 hom. )

Consequence

ZNF557
NM_024341.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00100

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 made for transcript

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=0.01844728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF557	NM_024341.3 linkuse as main transcript	c.370G>A	p.Gly124Arg	missense_variant	7/8	ENST00000252840.11	NP_077317.2	Q8N988-2
ZNF557	NM_001044387.2 linkuse as main transcript	c.370G>A	p.Gly124Arg	missense_variant	7/8		NP_001037852.1	Q8N988-2
ZNF557	NM_001044388.2 linkuse as main transcript	c.349G>A	p.Gly117Arg	missense_variant	7/8		NP_001037853.1	Q8N988-1
ZNF557	XM_047439432.1 linkuse as main transcript	c.349G>A	p.Gly117Arg	missense_variant	7/8		XP_047295388.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF557	ENST00000252840.11 linkuse as main transcript	c.370G>A	p.Gly124Arg	missense_variant	7/8	1	NM_024341.3	ENSP00000252840.5		Q8N988-2
ZNF557	ENST00000414706.2 linkuse as main transcript	c.349G>A	p.Gly117Arg	missense_variant	7/8	2		ENSP00000404065.2		Q8N988-1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000445

AC:

111

AN:

249452

Hom.:

AF XY:

0.000392

AC XY:

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000883

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000809

AC:

1182

AN:

1461634

Hom.:

Cov.:

AF XY:

0.000726

AC XY:

528

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000977

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.000585

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00119

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000757

Hom.:

Bravo

AF:

0.000472

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00158

AC:

ExAC

AF:

0.000513

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2024

The c.370G>A (p.G124R) alteration is located in exon 7 (coding exon 5) of the ZNF557 gene. This alteration results from a G to A substitution at nucleotide position 370, causing the glycine (G) at amino acid position 124 to be replaced by an arginine (R). 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

0.13

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.71

CADD

Benign

8.9

DANN

Benign

0.26

DEOGEN2

Benign

0.012

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00061

LIST_S2

Benign

0.13

T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.69

.;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.59

N;.

REVEL

Benign

0.0070

Sift

Benign

0.43

T;.

Sift4G

Benign

0.33

T;T

Polyphen

0.0060

B;B

Vest4

0.15

MutPred

0.31

.;Gain of MoRF binding (P = 0.0148);

MVP

0.095

MPC

0.095

ClinPred

0.0075

GERP RS

-3.1

Varity_R

0.029

gMVP

0.075

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over