Variant X-46499968-T-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001190417.2(ZNF674):c.1606A>C(p.Ile536Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,090,695 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000021 ( 0 hom. 4 hem. )

Consequence

ZNF674
NM_001190417.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.233

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=0.12125951).

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF674	NM_001190417.2 linkuse as main transcript	c.1606A>C	p.Ile536Leu	missense_variant	6/6	ENST00000683375.1	NP_001177346.1	Q2M3X9A0A804HHU7
ZNF674	NM_001039891.3 linkuse as main transcript	c.1621A>C	p.Ile541Leu	missense_variant	6/6		NP_001034980.1	Q2M3X9-1
ZNF674	NM_001146291.2 linkuse as main transcript	c.1603A>C	p.Ile535Leu	missense_variant	6/6		NP_001139763.1	Q2M3X9-2
ZNF674	XM_011543943.4 linkuse as main transcript	c.1618A>C	p.Ile540Leu	missense_variant	6/6		XP_011542245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF674	ENST00000683375.1 linkuse as main transcript	c.1606A>C	p.Ile536Leu	missense_variant	6/6		NM_001190417.2	ENSP00000506769.1	A0A804HHU7
ZNF674	ENST00000523374.5 linkuse as main transcript	c.1621A>C	p.Ile541Leu	missense_variant	6/6	1		ENSP00000429148.1	Q2M3X9-1
ZNF674	ENST00000414387.6 linkuse as main transcript	c.1603A>C	p.Ile535Leu	missense_variant	5/5	3		ENSP00000428248.1	Q2M3X9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000230

AC:

AN:

173607

Hom.:

AF XY:

0.0000168

AC XY:

AN XY:

59651

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:

0.0000387

Gnomad OTH exome

AF:

0.000233

GnomAD4 exome

AF:

0.0000211

AC:

AN:

1090695

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

357207

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000524

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000263

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

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

Mar 21, 2024

The c.1621A>C (p.I541L) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a A to C substitution at nucleotide position 1621, causing the isoleucine (I) at amino acid position 541 to be replaced by a leucine (L). 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

Benign

0.22

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.82

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.017

T;.

FATHMM_MKL

Benign

0.00011

LIST_S2

Benign

0.068

T;T

M_CAP

Benign

0.0022

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.59

N;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.016

Sift

Uncertain

0.020

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

0.24

B;.

Vest4

0.062

MutPred

0.41

Loss of methylation at K537 (P = 0.0467);.;

MVP

0.54

MPC

0.23

ClinPred

0.044

GERP RS

1.2

Varity_R

0.33

gMVP

0.034

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