rs869025582

Variant names:

• chr1-151287016-G-T
• rs869025582
• NM_020832.3:c.725G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_020832.3(ZNF687):​c.725G>T​(p.Ser242Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF687 NM_020832.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.367
• Publications: 3 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: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-151287016-G-T is Pathogenic according to our data. Variant chr1-151287016-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 222988.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23025966). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF687	NM_020832.3	MANE Select	c.725G>T	p.Ser242Ile	missense	Exon 2 of 9	NP_065883.1
	ZNF687	NM_001304763.2		c.725G>T	p.Ser242Ile	missense	Exon 3 of 10	NP_001291692.1
	ZNF687	NM_001304764.2		c.725G>T	p.Ser242Ile	missense	Exon 2 of 9	NP_001291693.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF687	ENST00000336715.11	TSL:1 MANE Select	c.725G>T	p.Ser242Ile	missense	Exon 2 of 9	ENSP00000336620.5
	ZNF687	ENST00000324048.9	TSL:1	c.725G>T	p.Ser242Ile	missense	Exon 3 of 10	ENSP00000319829.5
	ZNF687	ENST00000449313.5	TSL:5	n.725G>T		non_coding_transcript_exon	Exon 2 of 7	ENSP00000415286.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Paget disease of bone 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.37
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.082
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.32
MutPred		0.20		Loss of glycosylation at S242 (P = 0.0169)
MVP		0.20
MPC		0.59
ClinPred		0.17	T
GERP RS		4.6
PromoterAI		0.030	Neutral
Varity_R		0.13
gMVP		0.22
Mutation Taster		=20/80	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869025582; hg19: chr1-151259492;