X-46500238-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001190417.2(ZNF674):c.1336G>A(p.Gly446Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000498 in 1,205,109 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.000029 ( 0 hom. 9 hem. )

Consequence

ZNF674
NM_001190417.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.52

Publications

0 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014963359).

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2 link	c.1336G>A	p.Gly446Arg	missense_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1	Q2M3X9A0A804HHU7
ZNF674	NM_001039891.3 link	c.1351G>A	p.Gly451Arg	missense_variant	Exon 6 of 6		NP_001034980.1	Q2M3X9-1
ZNF674	NM_001146291.2 link	c.1333G>A	p.Gly445Arg	missense_variant	Exon 6 of 6		NP_001139763.1	Q2M3X9-2
ZNF674	XM_011543943.4 link	c.1348G>A	p.Gly450Arg	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.1336G>A	p.Gly446Arg	missense_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1	A0A804HHU7
ZNF674	ENST00000523374.5 link	c.1351G>A	p.Gly451Arg	missense_variant	Exon 6 of 6	1		ENSP00000429148.1	Q2M3X9-1
ZNF674	ENST00000414387.6 link	c.1333G>A	p.Gly445Arg	missense_variant	Exon 5 of 5	3		ENSP00000428248.1	Q2M3X9-2

Frequencies

GnomAD3 genomes

AF:

0.000260

AC:

AN:

107549

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000916

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000698

GnomAD2 exomes

AF:

0.0000827

AC:

AN:

181418

AF XY:

0.0000447

show subpopulations

Gnomad AFR exome

AF:

0.00104

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000292

AC:

AN:

1097502

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

362910

show subpopulations

African (AFR)

AF:

0.000947

AC:

AN:

26398

American (AMR)

AF:

0.0000568

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.00

AC:

AN:

30184

South Asian (SAS)

AF:

0.00

AC:

AN:

54113

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841583

Other (OTH)

AF:

0.0000651

AC:

AN:

46068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000260

AC:

AN:

107607

Hom.:

Cov.:

AF XY:

0.000287

AC XY:

AN XY:

31387

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

29541

American (AMR)

AF:

0.00

AC:

AN:

10118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2595

East Asian (EAS)

AF:

0.00

AC:

AN:

3334

South Asian (SAS)

AF:

0.00

AC:

AN:

2465

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5753

Middle Eastern (MID)

AF:

0.00

AC:

AN:

179

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51518

Other (OTH)

AF:

0.000690

AC:

AN:

1449

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000144

Hom.:

ESP6500AA

AF:

0.00105

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000989

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1351G>A (p.G451R) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a G to A substitution at nucleotide position 1351, causing the glycine (G) at amino acid position 451 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.5

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.014

T;.

FATHMM_MKL

Benign

0.000020

LIST_S2

Benign

0.087

T;T

M_CAP

Benign

0.0010

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.67

N;.

PhyloP100

-1.5

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.044

Sift

Benign

0.20

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.14

B;.

Vest4

0.053

MutPred

0.35

Gain of MoRF binding (P = 0.0118);.;

MVP

0.57

MPC

0.84

ClinPred

0.063

GERP RS

-0.099

Varity_R

0.075

gMVP

0.081

Mutation Taster

=99/1

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

X-46500238-C-T

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