rs886037825

Variant names:

• chrX-153504869-G-A
• rs886037825
• NM_001711.6:c.238G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001711.6(BGN):​c.238G>A​(p.Gly80Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G80D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: BGN NM_001711.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.51
• 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: Likely_pathogenic. The variant received 7 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-153504869-G-A is Pathogenic according to our data. Variant chrX-153504869-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265798.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BGN	NM_001711.6	c.238G>A	p.Gly80Ser	missense_variant, splice_region_variant	Exon 2 of 8	ENST00000331595.9	NP_001702.1
BGN	XM_017029724.3	c.238G>A	p.Gly80Ser	missense_variant, splice_region_variant	Exon 1 of 7		XP_016885213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BGN	ENST00000331595.9	c.238G>A	p.Gly80Ser	missense_variant, splice_region_variant	Exon 2 of 8	1	NM_001711.6	ENSP00000327336.4
BGN	ENST00000431891.1	c.238G>A	p.Gly80Ser	missense_variant, splice_region_variant	Exon 2 of 5	5		ENSP00000402525.1
BGN	ENST00000472615.5	n.382G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 8	5
BGN	ENST00000480756.1	n.329+51G>A		intron_variant	Intron 2 of 7	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

- -

Meester-Loeys syndrome Pathogenic:1

May 10, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

X-linked spondyloepimetaphyseal dysplasia;C4310811:Meester-Loeys syndrome Pathogenic:1

Apr 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.238G>A variant (also known as p.G80S), located in coding exon 1 of the BGN gene, results from a G to A substitution at nucleotide position 238. The glycine at codon 80 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. This variant was reported hemizygous in male proband with some features consistent with Meester-Loeys syndrome, and RNA studies indicated that this alteration resulted in abnormal splicing (Meester JA et al. Genet Med, 2017 Apr;19:386-395; Meester JAN et al. NPJ Genom Med, 2024 Mar;9:22). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. However, loss of function of BGN has not been established as a mechanism of disease. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.3	L;.
PhyloP100		4.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.029	D;D
Sift4G	Uncertain	0.048	D;D
Polyphen		0.98	D;.
Vest4		0.24
MutPred		0.62		Gain of disorder (P = 0.0416);Gain of disorder (P = 0.0416);
MVP		0.97
MPC		0.37
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.62
gMVP		0.43
Mutation Taster		=14/86	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886037825; hg19: chrX-152770327;