chr17-43753993-CT-C

Variant names:

• chr17-43753993-CT-C
• rs563385804
• NM_025237.3:c.*1348delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_025237.3(SOST):​c.*1348delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0738 in 148,718 control chromosomes in the GnomAD database, including 1,337 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.074 (1337 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (0 hom.)
• Consequence: SOST NM_025237.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.83
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 17-43753993-CT-C is Benign according to our data. Variant chr17-43753993-CT-C is described in CliVar as Benign. Clinvar id is 323429.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOST	NM_025237.3	c.*1348delA		3_prime_UTR_variant	Exon 2 of 2	ENST00000301691.3	NP_079513.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOST	ENST00000301691.3	c.*1348delA		3_prime_UTR_variant	Exon 2 of 2	1	NM_025237.3	ENSP00000301691.1

Frequencies

GnomAD3 genomes AF: 0.0736 AC: 10911 AN: 148228 Hom.: 1318 Cov.: 31

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.00469

Gnomad EAS AF: 0.000783

Gnomad SAS AF: 0.00191

Gnomad FIN AF: 0.000628

Gnomad MID AF: 0.0162

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.0523

GnomAD4 exome AF: 0.00253 AC: 1 AN: 396 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 242

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00256 AC: 1 AN: 390

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0740 AC: 10975 AN: 148322 Hom.: 1337 Cov.: 31 AF XY: 0.0712 AC XY: 5145 AN XY: 72244

African (AFR) AF: 0.254 AC: 10391 AN: 40848

American (AMR) AF: 0.0236 AC: 350 AN: 14822

Ashkenazi Jewish (ASJ) AF: 0.00469 AC: 16 AN: 3412

East Asian (EAS) AF: 0.000786 AC: 4 AN: 5092

South Asian (SAS) AF: 0.00192 AC: 9 AN: 4684

European-Finnish (FIN) AF: 0.000628 AC: 6 AN: 9556

Middle Eastern (MID) AF: 0.0176 AC: 5 AN: 284

European-Non Finnish (NFE) AF: 0.00132 AC: 88 AN: 66674

Other (OTH) AF: 0.0518 AC: 106 AN: 2046

Alfa AF: 0.000132 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary bone dysplasia with increased bone density Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.8
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: rs563385804; hg19: chr17-41831361; COSMIC: COSV57013327;