rs148402804

Variant names:

• chr1-151289853-C-A
• rs148402804
• NM_020832.3:c.2810C>A
• ZNF687 p.Pro937His

Your query was ambiguous. Multiple possible variants found:

• chr1-151289853-C-A
• chr1-151289853-C-G
• chr1-151289853-C-T

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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:4
• 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: Likely_benign. The variant received -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 VariationId is 222987.
• BP4: Computational evidence support a benign effect (MetaRNN=0.044634283).
• BS2: High AC in GnomAd4 at 31 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>A	p.Pro937His	missense	Exon 6 of 9	NP_065883.1	Q8N1G0-1
	ZNF687	NM_001304763.2		c.2810C>A	p.Pro937His	missense	Exon 7 of 10	NP_001291692.1	Q8N1G0-1
	ZNF687	NM_001304764.2		c.2810C>A	p.Pro937His	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>A	p.Pro937His	missense	Exon 6 of 9	ENSP00000336620.5	Q8N1G0-1
	ZNF687	ENST00000324048.9	TSL:1	c.2810C>A	p.Pro937His	missense	Exon 7 of 10	ENSP00000319829.5	Q8N1G0-1
	ZNF687	ENST00000853018.1		c.2810C>A	p.Pro937His	missense	Exon 6 of 9	ENSP00000523077.1

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

GnomAD2 exomes AF: 0.000245 AC: 43 AN: 175820 AF XY: 0.000191

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 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

African (AFR) AF: 0.0000310 AC: 1 AN: 32288

American (AMR) AF: 0.000318 AC: 12 AN: 37764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25314

East Asian (EAS) AF: 0.000108 AC: 4 AN: 37052

South Asian (SAS) AF: 0.000148 AC: 12 AN: 81136

European-Finnish (FIN) AF: 0.0000399 AC: 2 AN: 50106

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5706

European-Non Finnish (NFE) AF: 0.000266 AC: 289 AN: 1087836

Other (OTH) AF: 0.000222 AC: 13 AN: 58626

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

African (AFR) AF: 0.0000962 AC: 4 AN: 41588

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

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

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

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Paget disease of bone 6 (3)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.047	D
Varity_R		0.16
gMVP		0.50
Mutation Taster		=54/46	polymorphism

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

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;