17-43755022-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_025237.3(SOST):c.*320C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 353,596 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (26 hom., cov: 32)
  • Exomes 𝑓: 0.015 (27 hom.)
• Consequence: SOST NM_025237.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.52

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-43755022-G-A is Benign according to our data. Variant chr17-43755022-G-A is described in ClinVar as [Benign]. Clinvar id is 892296.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1953/152292) while in subpopulation NFE AF= 0.0197 (1337/68010). AF 95% confidence interval is 0.0188. There are 26 homozygotes in gnomad4. There are 923 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOST	NM_025237.3	c.*320C>T		3_prime_UTR_variant	2/2	ENST00000301691.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOST	ENST00000301691.3	c.*320C>T		3_prime_UTR_variant	2/2	1	NM_025237.3	P1

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1954 AN: 152174 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.0152 AC: 3053 AN: 201304 Hom.: 27 Cov.: 0 AF XY: 0.0158 AC XY: 1632 AN XY: 102990

Gnomad4 AFR exome AF: 0.00309

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.00198

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0185

Gnomad4 FIN exome AF: 0.0148

Gnomad4 NFE exome AF: 0.0180

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0128 AC: 1953 AN: 152292 Hom.: 26 Cov.: 32 AF XY: 0.0124 AC XY: 923 AN XY: 74480

Gnomad4 AFR AF: 0.00339

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0184

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0166 Hom.: 2

Bravo AF: 0.0116

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sclerosteosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	9.9
Dann	Benign	0.82

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: rs17883310; hg19: chr17-41832390;