chr17-43754338-C-T

Position:

• chr17-43754338-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025237.3(SOST):​c.*1004G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0942 in 144,198 control chromosomes in the GnomAD database, including 1,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (1998 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOST NM_025237.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.923

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 17-43754338-C-T is Benign according to our data. Variant chr17-43754338-C-T is described in ClinVar as [Benign]. Clinvar id is 323432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOST	NM_025237.3	c.*1004G>A		3_prime_UTR_variant	2/2	ENST00000301691.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOST	ENST00000301691.3	c.*1004G>A		3_prime_UTR_variant	2/2	1	NM_025237.3	P1

Frequencies

GnomAD3 genomes AF: 0.0937 AC: 13495 AN: 144076 Hom.: 1966 Cov.: 29

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.000826

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.00206

Gnomad MID AF: 0.0514

Gnomad NFE AF: 0.00581

Gnomad OTH AF: 0.0735

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 52 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 30

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0942 AC: 13579 AN: 144198 Hom.: 1998 Cov.: 29 AF XY: 0.0919 AC XY: 6398 AN XY: 69592

Gnomad4 AFR AF: 0.319

Gnomad4 AMR AF: 0.0423

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.000827

Gnomad4 SAS AF: 0.00598

Gnomad4 FIN AF: 0.00206

Gnomad4 NFE AF: 0.00581

Gnomad4 OTH AF: 0.0729

Alfa AF: 0.0597 Hom.: 269

Bravo AF: 0.109

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.97
CADD	Benign	1.7
DANN	Benign	0.50

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: rs17886183; hg19: chr17-41831706;