17-43758681-C-T

Position:

• chr17-43758681-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_025237.3(SOST):​c.61G>A​(p.Val21Met) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOST NM_025237.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.65

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745
• PP5: Variant 17-43758681-C-T is Pathogenic according to our data. Variant chr17-43758681-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31592.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOST	NM_025237.3	c.61G>A	p.Val21Met	missense_variant	1/2	ENST00000301691.3	NP_079513.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOST	ENST00000301691.3	c.61G>A	p.Val21Met	missense_variant	1/2	1	NM_025237.3	ENSP00000301691.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Craniodiaphyseal dysplasia, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2011

- -

SOST-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2023

The SOST c.61G>A variant is predicted to result in the amino acid substitution p.Val21Met. This variant was reported to occur de novo in an individual with autosomal dominant craniodiaphyseal dysplasia (Kim et al 2011. PubMed ID: 21221996). In addition, an alternative amino acid substitution at this position (c.61G>T, p.Val21Leu) was also reported in a patient with presumed autosomal dominant craniodiaphyseal dysplasia (Kim et al 2011. PubMed ID: 21221996). Functional studies with both variants indicate the p.Val21 residue is part of the secretion signal of the protein and disrupts sclerostin secretion (Kim et al 2011. PubMed ID: 21221996). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.32	N
REVEL	Uncertain	0.49
Sift	Uncertain	0.018	D
Sift4G	Benign	0.066	T
Polyphen		0.37	B
Vest4		0.72
MutPred		0.58		Loss of sheet (P = 0.0037);
MVP		0.96
MPC		1.4
ClinPred		0.60	D
GERP RS		3.5
Varity_R		0.087
gMVP		0.34

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: rs387907169; hg19: chr17-41836049;