NM_001190417.2:c.1115G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001190417.2(ZNF674):c.1115G>A(p.Arg372Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,604 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

ZNF674
NM_001190417.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.40

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08948159).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF674	NM_001190417.2 link	c.1115G>A	p.Arg372Lys	missense_variant	Exon 6 of 6	ENST00000683375.1	NP_001177346.1	Q2M3X9A0A804HHU7
ZNF674	NM_001039891.3 link	c.1130G>A	p.Arg377Lys	missense_variant	Exon 6 of 6		NP_001034980.1	Q2M3X9-1
ZNF674	NM_001146291.2 link	c.1112G>A	p.Arg371Lys	missense_variant	Exon 6 of 6		NP_001139763.1	Q2M3X9-2
ZNF674	XM_011543943.4 link	c.1127G>A	p.Arg376Lys	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.1115G>A	p.Arg372Lys	missense_variant	Exon 6 of 6		NM_001190417.2	ENSP00000506769.1	A0A804HHU7
ZNF674	ENST00000523374.5 link	c.1130G>A	p.Arg377Lys	missense_variant	Exon 6 of 6	1		ENSP00000429148.1	Q2M3X9-1
ZNF674	ENST00000414387.6 link	c.1112G>A	p.Arg371Lys	missense_variant	Exon 5 of 5	3		ENSP00000428248.1	Q2M3X9-2

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112604

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000645

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.11e-7

AC:

AN:

1097882

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363324

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26396

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19384

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.00

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841835

Other (OTH)

AF:

0.00

AC:

AN:

46073

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112604

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34752

show subpopulations

African (AFR)

AF:

0.0000645

AC:

AN:

31006

American (AMR)

AF:

0.00

AC:

AN:

10626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3589

South Asian (SAS)

AF:

0.00

AC:

AN:

2759

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53391

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1130G>A (p.R377K) alteration is located in exon 6 (coding exon 4) of the ZNF674 gene. This alteration results from a G to A substitution at nucleotide position 1130, causing the arginine (R) at amino acid position 377 to be replaced by a lysine (K). 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

0.12

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.38

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.021

T;.

FATHMM_MKL

Benign

0.000060

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.00087

MetaRNN

Benign

0.089

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

L;.

PhyloP100

-3.4

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.0030

Sift

Benign

0.11

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.0010

B;.

Vest4

0.058

MutPred

0.39

Gain of methylation at R377 (P = 0.0071);.;

MVP

0.30

MPC

0.21

ClinPred

0.10

GERP RS

-4.5

Varity_R

0.081

gMVP

0.062

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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NM_001190417.2:c.1115G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over