rs886037824

Variant names:

• chrX-153507184-A-C
• rs886037824
• NM_001711.6:c.908A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001711.6(BGN):​c.908A>C​(p.Gln303Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: BGN NM_001711.6 missense, splice_region
• Scores: Splicing: ADA: 0.9868
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 1.77
• Publications: 3 publications found

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]

BGN Gene-Disease associations (from GenCC):

• Meester-Loeys syndrome

  Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Illumina, G2P
• X-linked spondyloepimetaphyseal dysplasia

  Inheritance: XL Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BGN	NM_001711.6	c.908A>C	p.Gln303Pro	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000331595.9	NP_001702.1
BGN	XM_017029724.3	c.908A>C	p.Gln303Pro	missense_variant, splice_region_variant	Exon 6 of 7		XP_016885213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BGN	ENST00000331595.9	c.908A>C	p.Gln303Pro	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_001711.6	ENSP00000327336.4
BGN	ENST00000472615.5	n.925A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 8	5
BGN	ENST00000480756.1	n.978A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 8	5
BGN	ENST00000492658.1	n.294+570A>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Meester-Loeys syndrome Pathogenic:1 Uncertain:1

May 10, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PM8 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

-

Centre of Medical Genetics, University of Antwerp

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.53		Gain of ubiquitination at K300 (P = 0.0822);
MVP		0.98
MPC		1.1
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.84
gMVP		0.88
Mutation Taster		=60/40	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.020		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: rs886037824; hg19: chrX-152772642;