rs148402804

chr1-151289853-C-Achr1-151289853-C-Gchr1-151289853-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5 BP4_Strong BS2

The NM_020832.3(ZNF687):c.2810C>A(p.Pro937His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000233 in 1,568,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P937R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: ZNF687 NM_020832.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.81

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: 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: {Pathogenic=1, Uncertain_significance=2, Likely_pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.044634283).
• BS2: High AC in GnomAd at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF687	NM_020832.3	c.2810C>A	p.Pro937His	missense_variant	6/9	ENST00000336715.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF687	ENST00000336715.11	c.2810C>A	p.Pro937His	missense_variant	6/9	1	NM_020832.3	P1
ZNF687	ENST00000324048.9	c.2810C>A	p.Pro937His	missense_variant	7/10	1		P1
ZNF687	ENST00000426871.1	c.1619C>A	p.Pro540His	missense_variant	5/8	2
ZNF687	ENST00000449313.5	c.*112C>A		3_prime_UTR_variant, NMD_transcript_variant	4/7	5

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000245 AC: 43 AN: 175820 Hom.: 0 AF XY: 0.000191 AC XY: 18 AN XY: 94262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000375

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000152

Gnomad SAS exome AF: 0.000244

Gnomad FIN exome AF: 0.0000610

Gnomad NFE exome AF: 0.000333

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000236 AC: 334 AN: 1415828 Hom.: 0 Cov.: 34 AF XY: 0.000230 AC XY: 161 AN XY: 700252

Gnomad4 AFR exome AF: 0.0000310

Gnomad4 AMR exome AF: 0.000318

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000108

Gnomad4 SAS exome AF: 0.000148

Gnomad4 FIN exome AF: 0.0000399

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.000222

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74486

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.000189

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000160 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paget disease of bone 6 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 02, 2020	This ZNF687 variant (rs148402804) is present in a large population dataset (gnomAD: 50/207220 total alleles; 0.02%; no homozygotes) and has not been reported in the literature, to our knowledge. This variant has been reported in ClinVar. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be tolerated. The proline residue at this position is evolutionarily conserved across most species assessed. A different amino acid change at this position (p.Pro937Arg) has been reported in multiple families with Paget disease of bone 6. Due to insufficient evidence, we consider the clinical significance of c.2810C>A to be uncertain at this time. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2023

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 937 of the ZNF687 protein (p.Pro937His). This variant is present in population databases (rs148402804, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ZNF687-related conditions. ClinVar contains an entry for this variant (Variation ID: 801543). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.047	D;D
Polyphen		0.90	P;P
Vest4		0.29
MVP		0.093
MPC		0.71
ClinPred		0.087	T
GERP RS		2.1
Varity_R		0.16
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs148402804; hg19: chr1-151262329;