chrX-153504671-AG-A

Position:

• chrX-153504671-AG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000331595.9(BGN):​c.41del​(p.Ser14ThrfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: BGN ENST00000331595.9 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.45

Genes affected

BGN (HGNC:1044): (biglycan) This gene encodes a member of the small leucine-rich proteoglycan (SLRP) family of proteins. The encoded preproprotein is proteolytically processed to generate the mature protein, which plays a role in bone growth, muscle development and regeneration, and collagen fibril assembly in multiple tissues. This protein may also regulate inflammation and innate immunity. Additionally, the encoded protein may contribute to atherosclerosis and aortic valve stenosis in human patients. This gene and the related gene decorin are thought to be the result of a gene duplication. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-153504671-AG-A is Pathogenic according to our data. Variant chrX-153504671-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817331.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BGN	NM_001711.6	c.41del	p.Ser14ThrfsTer22	frameshift_variant	2/8	ENST00000331595.9	NP_001702.1
BGN	XM_017029724.3	c.41del	p.Ser14ThrfsTer22	frameshift_variant	1/7		XP_016885213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BGN	ENST00000331595.9	c.41del	p.Ser14ThrfsTer22	frameshift_variant	2/8	1	NM_001711.6	ENSP00000327336	P1
BGN	ENST00000431891.1	c.41del	p.Ser14ThrfsTer22	frameshift_variant	2/5	5		ENSP00000402525
BGN	ENST00000472615.5	n.185del		non_coding_transcript_exon_variant	2/8	5
BGN	ENST00000480756.1	n.183del		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 28, 2018

Although the c.41delG likely pathogenic variant in the BGN gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon serine 14, changing it to a threonine, and creating a premature stop codon at position 22 of the new reading frame, denoted p.Ser14ThrfsX22. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Furthermore, the c.41delG variant has not been observed in large population cohorts (Lek et al., 2016). However, only one other loss of function variant in the BGN gene has been reported in Human Gene Mutation Database in association with BGN-related disorders (Stenson et al., 2014). In summary, c.41delG in the BGN gene is interpreted as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1602981402; hg19: chrX-152770129;