rs865429

Positions:

• chr17-43757847-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025237.3(SOST):​c.220+675C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.815 in 152,178 control chromosomes in the GnomAD database, including 51,356 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.81 (51356 hom., cov: 32)
• Consequence: SOST NM_025237.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.813

Genes affected

SOST (HGNC:13771): (sclerostin) Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Loss-of-function mutations in this gene are associated with an autosomal-recessive disorder, sclerosteosis, which causes progressive bone overgrowth. A deletion downstream of this gene, which causes reduced sclerostin expression, is associated with a milder form of the disorder called van Buchem disease. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOST	NM_025237.3	c.220+675C>T		intron_variant		ENST00000301691.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOST	ENST00000301691.3	c.220+675C>T		intron_variant		1	NM_025237.3	P1

Frequencies

GnomAD3 genomes AF: 0.815 AC: 123886 AN: 152060 Hom.: 51318 Cov.: 32

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.931

Gnomad AMR AF: 0.876

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.754

Gnomad SAS AF: 0.857

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.816

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.815 AC: 123975 AN: 152178 Hom.: 51356 Cov.: 32 AF XY: 0.819 AC XY: 60980 AN XY: 74426

Gnomad4 AFR AF: 0.650

Gnomad4 AMR AF: 0.875

Gnomad4 ASJ AF: 0.844

Gnomad4 EAS AF: 0.754

Gnomad4 SAS AF: 0.857

Gnomad4 FIN AF: 0.928

Gnomad4 NFE AF: 0.882

Gnomad4 OTH AF: 0.818

Alfa AF: 0.870 Hom.: 75962

Bravo AF: 0.799

Asia WGS AF: 0.810 AC: 2820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.030
DANN	Benign	0.57

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: rs865429; hg19: chr17-41835215;