X-46500294-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: XL Classification: NO_KNOWN Submitted by: Ambry Genetics
X-linked intellectual disability
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ZNF674 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2 link	c.1280A>G	p.His427Arg	missense_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1	Q2M3X9A0A804HHU7
ZNF674	NM_001039891.3 link	c.1295A>G	p.His432Arg	missense_variant	Exon 6 of 6		NP_001034980.1	Q2M3X9-1
ZNF674	NM_001146291.2 link	c.1277A>G	p.His426Arg	missense_variant	Exon 6 of 6		NP_001139763.1	Q2M3X9-2
ZNF674	XM_011543943.4 link	c.1292A>G	p.His431Arg	missense_variant	Exon 6 of 6		XP_011542245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF674	ENST00000683375.1 link	c.1280A>G	p.His427Arg	missense_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1	A0A804HHU7
ZNF674	ENST00000523374.5 link	c.1295A>G	p.His432Arg	missense_variant	Exon 6 of 6	1		ENSP00000429148.1	Q2M3X9-1
ZNF674	ENST00000414387.6 link	c.1277A>G	p.His426Arg	missense_variant	Exon 5 of 5	3		ENSP00000428248.1	Q2M3X9-2

Frequencies

GnomAD3 genomes

AF:

0.00377

AC:

424

AN:

112430

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00104

AC:

189

AN:

181673

AF XY:

0.000743

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 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

African (AFR)

AF:

0.0123

AC:

324

AN:

26379

American (AMR)

AF:

0.000256

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19381

East Asian (EAS)

AF:

0.00

AC:

AN:

30191

South Asian (SAS)

AF:

0.0000370

AC:

AN:

54125

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40466

Middle Eastern (MID)

AF:

0.000726

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000250

AC:

AN:

841194

Other (OTH)

AF:

0.000478

AC:

AN:

46046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00380

AC:

427

AN:

112484

Hom.:

Cov.:

AF XY:

0.00364

AC XY:

126

AN XY:

34644

show subpopulations

African (AFR)

AF:

0.0133

AC:

411

AN:

31008

American (AMR)

AF:

0.000754

AC:

AN:

10616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3579

South Asian (SAS)

AF:

0.000366

AC:

AN:

2731

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

53279

Other (OTH)

AF:

0.00196

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00147

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

Jul 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ZNF674-related disorder

Benign:1

Jun 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.

PhyloP100

1.8

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

Mutation Taster

=98/2

polymorphism (auto)

(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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X-46500294-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over