rs869025582

Positions:

• chr1-151287016-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000336715.11(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. 14/21 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 ENST00000336715.11 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.367

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 Uncertain_significance. Variant got 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 id is 222988.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-151287016-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.23025966). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF687	NM_020832.3	c.725G>T	p.Ser242Ile	missense_variant	2/9	ENST00000336715.11	NP_065883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF687	ENST00000336715.11	c.725G>T	p.Ser242Ile	missense_variant	2/9	1	NM_020832.3	ENSP00000336620	P1
ZNF687	ENST00000324048.9	c.725G>T	p.Ser242Ile	missense_variant	3/10	1		ENSP00000319829	P1
ZNF687	ENST00000449313.5	c.725G>T	p.Ser242Ile	missense_variant, NMD_transcript_variant	2/7	5		ENSP00000415286

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Paget disease of bone 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 26, 2016

- -

Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.082
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	D;D
Vest4		0.32
MutPred		0.20		Loss of glycosylation at S242 (P = 0.0169);Loss of glycosylation at S242 (P = 0.0169);
MVP		0.20
MPC		0.59
ClinPred		0.17	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs869025582; hg19: chr1-151259492;