Variant X-46500750-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001190417.2(ZNF674):c.824A>G(p.Tyr275Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 1,203,391 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

ZNF674
NM_001190417.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.877

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30028257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZNF674	NM_001190417.2 linkuse as main transcript	c.824A>G	p.Tyr275Cys	missense_variant	6/6	ENST00000683375.1	NP_001177346.1
ZNF674	NM_001039891.3 linkuse as main transcript	c.839A>G	p.Tyr280Cys	missense_variant	6/6		NP_001034980.1
ZNF674	NM_001146291.2 linkuse as main transcript	c.821A>G	p.Tyr274Cys	missense_variant	6/6		NP_001139763.1
ZNF674	XM_011543943.4 linkuse as main transcript	c.836A>G	p.Tyr279Cys	missense_variant	6/6		XP_011542245.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF674	ENST00000683375.1 linkuse as main transcript	c.824A>G	p.Tyr275Cys	missense_variant	6/6		NM_001190417.2	ENSP00000506769	A1
ZNF674	ENST00000523374.5 linkuse as main transcript	c.839A>G	p.Tyr280Cys	missense_variant	6/6	1		ENSP00000429148	P4	Q2M3X9-1
ZNF674	ENST00000414387.6 linkuse as main transcript	c.821A>G	p.Tyr274Cys	missense_variant	5/5	3		ENSP00000428248	A1	Q2M3X9-2

Frequencies

GnomAD3 genomes

AF:

0.00000900

AC:

AN:

111128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33312

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1092263

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

358315

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000436

GnomAD4 genome

AF:

0.00000900

AC:

AN:

111128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

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

Feb 10, 2022

The c.839A>G (p.Y280C) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a A to G substitution at nucleotide position 839, causing the tyrosine (Y) at amino acid position 280 to be replaced by a cysteine (C). 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

0.60

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

T;.

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.22

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.21

MutPred

0.54

Loss of phosphorylation at Y280 (P = 0.0523);.;

MVP

0.93

MPC

0.86

ClinPred

0.99

GERP RS

0.88

Varity_R

0.65

gMVP

0.17

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