X-46499893-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001190417.2(ZNF674):c.1681T>C(p.Ser561Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,049,689 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. 6 hem. )

Consequence

ZNF674
NM_001190417.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.127

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15720704).

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ZNF674	NM_001190417.2 linkuse as main transcript	c.1681T>C	p.Ser561Pro	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3 linkuse as main transcript	c.1696T>C	p.Ser566Pro	missense_variant	6/6
ZNF674	NM_001146291.2 linkuse as main transcript	c.1678T>C	p.Ser560Pro	missense_variant	6/6
ZNF674	XM_011543943.4 linkuse as main transcript	c.1693T>C	p.Ser565Pro	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1 linkuse as main transcript	c.1681T>C	p.Ser561Pro	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5 linkuse as main transcript	c.1696T>C	p.Ser566Pro	missense_variant	6/6	1		P4	Q2M3X9-1
ZNF674	ENST00000414387.6 linkuse as main transcript	c.1678T>C	p.Ser560Pro	missense_variant	5/5	3		A1	Q2M3X9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000219

AC:

AN:

136836

Hom.:

AF XY:

0.0000513

AC XY:

AN XY:

38958

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000476

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1049689

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

335853

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000351

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000150

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2014

The p.S566P variant (also known as c.1696T>C), located in coding exon 4 of the ZNF674 gene, results from a T to C substitution at nucleotide position 1696. The serine at codon 566 is replaced by proline, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs372786285. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele was absent out of 2427 total male alleles studied. This amino acid position is not conserved on limited species alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.61

Cadd

Benign

Dann

Benign

0.90

DEOGEN2

Benign

0.045

T;.

FATHMM_MKL

Benign

0.000070

LIST_S2

Benign

0.21

T;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.2

D;D

REVEL

Benign

0.11

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.17

MVP

0.66

MPC

0.91

ClinPred

0.31

GERP RS

-0.041

Varity_R

0.68

gMVP

0.16

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