X-46500810-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001190417.2(ZNF674):c.764C>A(p.Ala255Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000587 in 1,193,493 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.000030 ( 0 hom. 9 hem. )

Consequence

ZNF674
NM_001190417.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.924

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040064305).

BS2

High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ZNF674	NM_001190417.2 linkuse as main transcript	c.764C>A	p.Ala255Asp	missense_variant	6/6	ENST00000683375.1
ZNF674	NM_001039891.3 linkuse as main transcript	c.779C>A	p.Ala260Asp	missense_variant	6/6
ZNF674	NM_001146291.2 linkuse as main transcript	c.761C>A	p.Ala254Asp	missense_variant	6/6
ZNF674	XM_011543943.4 linkuse as main transcript	c.776C>A	p.Ala259Asp	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF674	ENST00000683375.1 linkuse as main transcript	c.764C>A	p.Ala255Asp	missense_variant	6/6		NM_001190417.2	A1
ZNF674	ENST00000523374.5 linkuse as main transcript	c.779C>A	p.Ala260Asp	missense_variant	6/6	1		P4	Q2M3X9-1
ZNF674	ENST00000414387.6 linkuse as main transcript	c.761C>A	p.Ala254Asp	missense_variant	5/5	3		A1	Q2M3X9-2

Frequencies

GnomAD3 genomes

AF:

0.000346

AC:

AN:

109831

Hom.:

Cov.:

AF XY:

0.000218

AC XY:

AN XY:

32081

show subpopulations

Gnomad AFR

AF:

0.00123

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:

0.0000190

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000101

AC:

AN:

158881

Hom.:

AF XY:

0.0000595

AC XY:

AN XY:

50399

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.0000407

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1083662

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

352450

show subpopulations

Gnomad4 AFR exome

AF:

0.000960

Gnomad4 AMR exome

AF:

0.0000911

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:

0.00

Gnomad4 OTH exome

AF:

0.0000878

GnomAD4 genome

AF:

0.000346

AC:

AN:

109831

Hom.:

Cov.:

AF XY:

0.000218

AC XY:

AN XY:

32081

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000190

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000570

ESP6500AA

AF:

0.000873

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000834

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

Sep 01, 2021

The c.779C>A (p.A260D) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a C to A substitution at nucleotide position 779, causing the alanine (A) at amino acid position 260 to be replaced by an aspartic acid (D). 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

0.57

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.65

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.055

T;.

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.0028

MetaRNN

Benign

0.040

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-4.3

D;D

REVEL

Benign

0.12

Sift

Benign

0.12

T;T

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.98

D;.

Vest4

0.24

MVP

0.89

MPC

0.76

ClinPred

0.13

GERP RS

2.1

Varity_R

0.76

gMVP

0.092

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