rs182004761

chrX-46500988-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 0.832

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Stoplost variant in NM_001190417.2 Downstream stopcodon found after 8 codons.
• BS2: High Hemizygotes in GnomAd at 91 XL gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00374 AC: 412 AN: 110253 Hom.: 0 Cov.: 22 AF XY: 0.00280 AC XY: 91 AN XY: 32507

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.: 1 AF XY: 0.00438 AC XY: 211 AN XY: 48206

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.: 16 Cov.: 31 AF XY: 0.00651 AC XY: 2296 AN XY: 352951

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.: 0 Cov.: 22 AF XY: 0.00279 AC XY: 91 AN XY: 32570

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.: 40

Bravo AF: 0.00361

ESP6500AA AF: 0.00159 AC: 5

ESP6500EA AF: 0.00612 AC: 39

ExAC AF: 0.00410 AC: 492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

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

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, criteria provided, single submitter

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	T
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	25
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.023	N
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

Other links and lift over

dbSNP: rs182004761; hg19: chrX-46360423;