chr17-43757847-G-A

Variant names:

• chr17-43757847-G-A
• rs865429
• NM_025237.3:c.220+675C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 publications found

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]

SOST Gene-Disease associations (from GenCC):

• sclerosteosis 1

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• craniodiaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hyperostosis corticalis generalisata

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• sclerosteosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• craniodiaphyseal dysplasia, autosomal dominant

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025237.3. 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
	SOST	NM_025237.3	MANE Select	c.220+675C>T		intron	N/A	NP_079513.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOST	ENST00000301691.3	TSL:1 MANE Select	c.220+675C>T		intron	N/A	ENSP00000301691.1

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

African (AFR) AF: 0.650 AC: 26972 AN: 41472

American (AMR) AF: 0.875 AC: 13379 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2932 AN: 3472

East Asian (EAS) AF: 0.754 AC: 3899 AN: 5172

South Asian (SAS) AF: 0.857 AC: 4137 AN: 4826

European-Finnish (FIN) AF: 0.928 AC: 9858 AN: 10618

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.882 AC: 59984 AN: 68008

Other (OTH) AF: 0.818 AC: 1729 AN: 2114

Alfa AF: 0.863 Hom.: 98112

Bravo AF: 0.799

Asia WGS AF: 0.810 AC: 2820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.030
DANN	Benign	0.57
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

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: rs865429; hg19: chr17-41835215;