X-46500294-T-C

Position:

chrX-46500294-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001190417.2(ZNF674):c.1280A>G(p.His427Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000668 in 1,209,606 control chromosomes in the GnomAD database, including 7 homozygotes. There are 232 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., 126 hem., cov: 23)

Exomes 𝑓: 0.00035 ( 3 hom. 106 hem. )

Consequence

ZNF674
NM_001190417.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.78

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057187676).

BP6

Variant X-46500294-T-C is Benign according to our data. Variant chrX-46500294-T-C is described in ClinVar as [Benign]. Clinvar id is 130842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZNF674	NM_001190417.2 linkuse as main transcript	c.1280A>G	p.His427Arg	missense_variant	6/6	ENST00000683375.1	NP_001177346.1
ZNF674	NM_001039891.3 linkuse as main transcript	c.1295A>G	p.His432Arg	missense_variant	6/6		NP_001034980.1
ZNF674	NM_001146291.2 linkuse as main transcript	c.1277A>G	p.His426Arg	missense_variant	6/6		NP_001139763.1
ZNF674	XM_011543943.4 linkuse as main transcript	c.1292A>G	p.His431Arg	missense_variant	6/6		XP_011542245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF674	ENST00000683375.1 linkuse as main transcript	c.1280A>G	p.His427Arg	missense_variant	6/6		NM_001190417.2	ENSP00000506769	A1
ZNF674	ENST00000523374.5 linkuse as main transcript	c.1295A>G	p.His432Arg	missense_variant	6/6	1		ENSP00000429148	P4	Q2M3X9-1
ZNF674	ENST00000414387.6 linkuse as main transcript	c.1277A>G	p.His426Arg	missense_variant	5/5	3		ENSP00000428248	A1	Q2M3X9-2

Frequencies

GnomAD3 genomes

AF:

0.00377

AC:

424

AN:

112430

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

123

AN XY:

34580

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000755

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000365

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00198

GnomAD3 exomes

AF:

0.00104

AC:

189

AN:

181673

Hom.:

AF XY:

0.000743

AC XY:

AN XY:

67303

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.000109

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:

0.0000247

Gnomad OTH exome

AF:

0.000449

GnomAD4 exome

AF:

0.000347

AC:

381

AN:

1097122

Hom.:

Cov.:

AF XY:

0.000292

AC XY:

106

AN XY:

362520

show subpopulations

Gnomad4 AFR exome

AF:

0.0123

Gnomad4 AMR exome

AF:

0.000256

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000370

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000250

Gnomad4 OTH exome

AF:

0.000478

GnomAD4 genome

AF:

0.00380

AC:

427

AN:

112484

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

126

AN XY:

34644

show subpopulations

Gnomad4 AFR

AF:

0.0133

Gnomad4 AMR

AF:

0.000754

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000366

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000751

Gnomad4 OTH

AF:

0.00196

Alfa

AF:

0.000507

Hom.:

Bravo

AF:

0.00442

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00122

AC:

148

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 08, 2013

- -

ZNF674-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2019

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

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.88

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0047

T;.

FATHMM_MKL

Benign

0.00023

LIST_S2

Benign

0.30

T;T

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.7

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.60

N;N

REVEL

Benign

0.041

Sift

Benign

0.031

D;D

Sift4G

Benign

0.14

T;T

Polyphen

0.052

B;.

Vest4

0.078

MVP

0.76

MPC

0.35

ClinPred

0.012

GERP RS

2.2

Varity_R

0.19

gMVP

0.094

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