Genetic Variant SOST:c.*1348dupA (chr17-43753993-C-CT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_025237.3(SOST):c.*1348dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 148,508 control chromosomes in the GnomAD database, including 30 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.013 ( 30 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SOST
NM_025237.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.83

Publications

0 publications found

Variant links:

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)

SOST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1934/148508) while in subpopulation AFR AF = 0.0435 (1779/40862). AF 95% confidence interval is 0.0419. There are 30 homozygotes in GnomAd4. There are 942 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 30 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOST	NM_025237.3 link	c.*1348dupA		3_prime_UTR_variant	Exon 2 of 2	ENST00000301691.3	NP_079513.1	Q9BQB4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOST	ENST00000301691.3 link	c.*1348dupA		3_prime_UTR_variant	Exon 2 of 2	1	NM_025237.3	ENSP00000301691.1		Q9BQB4-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1918

AN:

148418

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0433

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00600

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00215

Gnomad SAS

AF:

0.00106

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00649

Gnomad NFE

AF:

0.000419

Gnomad OTH

AF:

0.00986

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

406

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

244

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

400

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

GnomAD4 genome

AF:

0.0130

AC:

1934

AN:

148508

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

942

AN XY:

72336

show subpopulations

African (AFR)

AF:

0.0435

AC:

1779

AN:

40862

American (AMR)

AF:

0.00599

AC:

AN:

14854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00216

AC:

AN:

5096

South Asian (SAS)

AF:

0.00107

AC:

AN:

4678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9612

Middle Eastern (MID)

AF:

0.00704

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000419

AC:

AN:

66760

Other (OTH)

AF:

0.00978

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

174

262

349

436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over