1-151289853-C-G

Variant names:

• chr1-151289853-C-G
• rs148402804
• NM_020832.3:c.2810C>G
• ZNF687 p.Pro937Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PS3 PP5 BP4 BS2

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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002557966: Gain of function has specifically been demonstrated for the p.(Pro987Arg) variant (PMID:26849110).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P937L) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 1.81
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Paget disease of bone 6

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002557966: Gain of function has specifically been demonstrated for the p.(Pro987Arg) variant (PMID: 26849110).
• 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 VariationId is 222987.
• 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 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020832.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF687	NM_020832.3	MANE Select	c.2810C>G	p.Pro937Arg	missense	Exon 6 of 9	NP_065883.1	Q8N1G0-1
	ZNF687	NM_001304763.2		c.2810C>G	p.Pro937Arg	missense	Exon 7 of 10	NP_001291692.1	Q8N1G0-1
	ZNF687	NM_001304764.2		c.2810C>G	p.Pro937Arg	missense	Exon 6 of 9	NP_001291693.1	Q8N1G0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF687	ENST00000336715.11	TSL:1 MANE Select	c.2810C>G	p.Pro937Arg	missense	Exon 6 of 9	ENSP00000336620.5	Q8N1G0-1
	ZNF687	ENST00000324048.9	TSL:1	c.2810C>G	p.Pro937Arg	missense	Exon 7 of 10	ENSP00000319829.5	Q8N1G0-1
	ZNF687	ENST00000853018.1		c.2810C>G	p.Pro937Arg	missense	Exon 6 of 9	ENSP00000523077.1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152206 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000210 AC: 37 AN: 175820 AF XY: 0.000180

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 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.: 0 Cov.: 34 AF XY: 0.000179 AC XY: 125 AN XY: 700252

African (AFR) AF: 0.000836 AC: 27 AN: 32288

American (AMR) AF: 0.000106 AC: 4 AN: 37764

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25314

East Asian (EAS) AF: 0.000459 AC: 17 AN: 37052

South Asian (SAS) AF: 0.000308 AC: 25 AN: 81136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.000136 AC: 148 AN: 1087836

Other (OTH) AF: 0.000341 AC: 20 AN: 58626

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74486

African (AFR) AF: 0.00108 AC: 45 AN: 41588

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68024

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000484

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	1	-	Paget disease of bone 6 (6)
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.066
Sift	Benign	0.042	D
Sift4G	Benign	0.084	T
Varity_R		0.083
gMVP		0.55
Mutation Taster		=3/97	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs148402804;

hg19: chr1-151262329;