X-46500988-G-A

Position:

chrX-46500988-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001190417.2(ZNF674):c.586C>T(p.Arg196Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,192,467 control chromosomes in the GnomAD database, including 16 homozygotes. There are 2,387 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., 91 hem., cov: 22)

Exomes 𝑓: 0.0065 ( 16 hom. 2296 hem. )

Consequence

ZNF674
NM_001190417.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 0.832

Variant links:

Genes affected

ZNF674 (HGNC:17625): (zinc finger protein 674) This gene encodes a zinc finger protein with an N-terminal Kruppel-associated box-containing (KRAB) domain and 11 Kruppel-type C2H2 zinc finger domains. Like other zinc finger proteins, this gene may function as a transcription factor. This gene resides on an area of chromosome X that has been implicated in nonsyndromic X-linked cognitive disabilities. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]

ZNF674 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 91 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ZNF674	NM_001190417.2 linkuse as main transcript	c.586C>T	p.Arg196Ter	stop_gained	6/6	ENST00000683375.1
ZNF674	NM_001039891.3 linkuse as main transcript	c.601C>T	p.Arg201Ter	stop_gained	6/6
ZNF674	NM_001146291.2 linkuse as main transcript	c.583C>T	p.Arg195Ter	stop_gained	6/6
ZNF674	XM_011543943.4 linkuse as main transcript	c.598C>T	p.Arg200Ter	stop_gained	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1 linkuse as main transcript	c.586C>T	p.Arg196Ter	stop_gained	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5 linkuse as main transcript	c.601C>T	p.Arg201Ter	stop_gained	6/6	1		P4	Q2M3X9-1
ZNF674	ENST00000414387.6 linkuse as main transcript	c.583C>T	p.Arg195Ter	stop_gained	5/5	3		A1	Q2M3X9-2

Frequencies

GnomAD3 genomes

AF:

0.00374

AC:

412

AN:

110253

Hom.:

Cov.:

AF XY:

0.00280

AC XY:

AN XY:

32507

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00166

Gnomad ASJ

AF:

0.00607

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00347

Gnomad FIN

AF:

0.00139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00618

Gnomad OTH

AF:

0.00203

GnomAD3 exomes

AF:

0.00380

AC:

587

AN:

154330

Hom.:

AF XY:

0.00438

AC XY:

211

AN XY:

48206

show subpopulations

Gnomad AFR exome

AF:

0.000643

Gnomad AMR exome

AF:

0.00178

Gnomad ASJ exome

AF:

0.00600

Gnomad EAS exome

AF:

0.0000843

Gnomad SAS exome

AF:

0.00206

Gnomad FIN exome

AF:

0.00131

Gnomad NFE exome

AF:

0.00650

Gnomad OTH exome

AF:

0.00404

GnomAD4 exome

AF:

0.00652

AC:

7056

AN:

1082161

Hom.:

Cov.:

AF XY:

0.00651

AC XY:

2296

AN XY:

352951

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.00535

Gnomad4 EAS exome

AF:

0.0000336

Gnomad4 SAS exome

AF:

0.00203

Gnomad4 FIN exome

AF:

0.00212

Gnomad4 NFE exome

AF:

0.00774

Gnomad4 OTH exome

AF:

0.00506

GnomAD4 genome

AF:

0.00374

AC:

412

AN:

110306

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

AN XY:

32570

show subpopulations

Gnomad4 AFR

AF:

0.00109

Gnomad4 AMR

AF:

0.00165

Gnomad4 ASJ

AF:

0.00607

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00348

Gnomad4 FIN

AF:

0.00139

Gnomad4 NFE

AF:

0.00618

Gnomad4 OTH

AF:

0.00200

Alfa

AF:

0.00555

Hom.:

Bravo

AF:

0.00361

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00612

AC:

ExAC

AF:

0.00410

AC:

492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 24, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 06, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency 0.98% in European population (ExAC) with 55 hemizygotes -

ZNF674-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.99

FATHMM_MKL

Benign

0.023

MutationTaster

Benign

1.0

D;D

Vest4

0.078

GERP RS

0.93

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

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