Genetic Variant ZNF674:p.Arg345Ile (chrX-46500540-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001190417.2(ZNF674):c.1034G>T(p.Arg345Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000082 in 1,097,491 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R345K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000082 ( 0 hom. 4 hem. )

Consequence

ZNF674
NM_001190417.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0490

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17430457).

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2 link	c.1034G>T	p.Arg345Ile	missense_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1	Q2M3X9A0A804HHU7
ZNF674	NM_001039891.3 link	c.1049G>T	p.Arg350Ile	missense_variant	Exon 6 of 6		NP_001034980.1	Q2M3X9-1
ZNF674	NM_001146291.2 link	c.1031G>T	p.Arg344Ile	missense_variant	Exon 6 of 6		NP_001139763.1	Q2M3X9-2
ZNF674	XM_011543943.4 link	c.1046G>T	p.Arg349Ile	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.1034G>T	p.Arg345Ile	missense_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1	A0A804HHU7
ZNF674	ENST00000523374.5 link	c.1049G>T	p.Arg350Ile	missense_variant	Exon 6 of 6	1		ENSP00000429148.1	Q2M3X9-1
ZNF674	ENST00000414387.6 link	c.1031G>T	p.Arg344Ile	missense_variant	Exon 5 of 5	3		ENSP00000428248.1	Q2M3X9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1097491

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362927

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26395

American (AMR)

AF:

0.00

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19375

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54129

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40493

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000951

AC:

AN:

841505

Other (OTH)

AF:

0.0000217

AC:

AN:

46058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.69

CADD

Benign

6.3

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.073

T;.

FATHMM_MKL

Benign

0.000090

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.0032

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.4

M;.

PhyloP100

0.049

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Benign

0.077

Sift

Benign

0.031

D;D

Sift4G

Uncertain

0.053

T;T

Polyphen

0.30

B;.

Vest4

0.39

MutPred

0.51

Loss of solvent accessibility (P = 0.0022);.;

MVP

0.30

MPC

0.38

ClinPred

0.27

GERP RS

-1.6

Varity_R

0.15

gMVP

0.13

Mutation Taster

=98/2

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

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chrX-46500540-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over