1-151286637-G-A

Position:

• chr1-151286637-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_020832.3(ZNF687):​c.346G>A​(p.Gly116Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00636 in 1,614,190 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0066 (57 hom.)
• Consequence: ZNF687 NM_020832.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.20

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031077862).
• BP6: Variant 1-151286637-G-A is Benign according to our data. Variant chr1-151286637-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 779222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 667 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF687	NM_020832.3	c.346G>A	p.Gly116Arg	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.346G>A	p.Gly116Arg	missense_variant	2/9	1	NM_020832.3	ENSP00000336620.5
ZNF687	ENST00000324048.9	c.346G>A	p.Gly116Arg	missense_variant	3/10	1		ENSP00000319829.5
ZNF687	ENST00000443959.1	c.373G>A	p.Gly125Arg	missense_variant	2/2	1		ENSP00000395261.1
ZNF687	ENST00000449313.5	n.346G>A		non_coding_transcript_exon_variant	2/7	5		ENSP00000415286.1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152208 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00953

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00513 AC: 1290 AN: 251306 Hom.: 8 AF XY: 0.00564 AC XY: 766 AN XY: 135838

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00836

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00768

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00657 AC: 9602 AN: 1461864 Hom.: 57 Cov.: 33 AF XY: 0.00657 AC XY: 4778 AN XY: 727230

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00825

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00739

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152326 Hom.: 6 Cov.: 33 AF XY: 0.00426 AC XY: 317 AN XY: 74486

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00975

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00690

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00588 Hom.: 3

Bravo AF: 0.00416

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00530 AC: 643

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00660

EpiControl AF: 0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 07, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ZNF687: BP4, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.71	T;.;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.0	.;M;M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.13	.;B;B
Vest4		0.14, 0.13
MutPred		0.17		.;Gain of methylation at K114 (P = 0.0489);Gain of methylation at K114 (P = 0.0489);
MVP		0.16
MPC		0.38
ClinPred		0.018	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.093

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: rs112780836; hg19: chr1-151259113;