1-151289853-C-G

Position:

chr1-151289853-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_020832.3(ZNF687):c.2810C>G(p.Pro937Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,568,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P937H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

ZNF687
NM_020832.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 1.81

Variant links:

Genes affected

ZNF687 (HGNC:29277): (zinc finger protein 687) This gene encodes C2H2 zinc finger protein. The encoded protein may play a role in bone differentiation and development. Mutations in this gene are the cause of Paget disease of bone-6. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ZNF687 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 1-151289853-C-G is Pathogenic according to our data. Variant chr1-151289853-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 222987.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}. Variant chr1-151289853-C-G is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.025917321). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF687	NM_020832.3 linkuse as main transcript	c.2810C>G	p.Pro937Arg	missense_variant	6/9	ENST00000336715.11	NP_065883.1	Q8N1G0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF687	ENST00000336715.11 linkuse as main transcript	c.2810C>G	p.Pro937Arg	missense_variant	6/9	1	NM_020832.3	ENSP00000336620.5		Q8N1G0-1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000210

AC:

AN:

175820

Hom.:

AF XY:

0.000180

AC XY:

AN XY:

94262

show subpopulations

Gnomad AFR exome

AF:

0.000422

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000532

Gnomad SAS exome

AF:

0.000162

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000845

GnomAD4 exome

AF:

0.000171

AC:

242

AN:

1415828

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

125

AN XY:

700252

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.000106

Gnomad4 ASJ exome

AF:

0.0000395

Gnomad4 EAS exome

AF:

0.000459

Gnomad4 SAS exome

AF:

0.000308

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000136

Gnomad4 OTH exome

AF:

0.000341

GnomAD4 genome

AF:

0.000433

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000146

Hom.:

Bravo

AF:

0.000484

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00139

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000143

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Paget disease of bone 6

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a likely mechanism of disease in this gene and is associated with Paget disease of bone 6 (MIM#616833). Gain of function has specifically been demonstrated for the p.(Pro987Arg) variant (PMID: 26849110). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - Variant is heterozygous. (I) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 50 heterozygotes, 0 homozygotes). (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v3: 66 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated nuclear localization signal (PMID: 29493781). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Arg937His) variant has been classified as a VUS by clinical diagnostic laboratories (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well-reported in the Italian population and has been suggested to be a founder mutation (ClinVar, PMID: 26849110, 29493781). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2024	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 937 of the ZNF687 protein (p.Pro937Arg). This variant is present in population databases (rs148402804, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Paget disease (PMID: 26849110, 29493781). ClinVar contains an entry for this variant (Variation ID: 222987). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.017

T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.67

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.50

.;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.69

N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.49

N;N

REVEL

Benign

0.066

Sift

Benign

0.042

D;D

Sift4G

Benign

0.084

T;T

Polyphen

0.0020

B;B

Vest4

0.46

MVP

0.082

MPC

0.34

ClinPred

0.0083

GERP RS

2.1

Varity_R

0.083

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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