rs886037825

Variant names:

• chrX-153504869-G-A
• rs886037825
• NM_001711.6:c.238G>A
• BGN p.Gly80Ser

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. G80V) 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:2
• 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: Illumina, Genomics England PanelApp, G2P, Ambry Genetics
• X-linked spondyloepimetaphyseal dysplasia

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

  Inheritance: Unknown 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 VariationId is 265798.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001711.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BGN	NM_001711.6	MANE Select	c.238G>A	p.Gly80Ser	missense splice_region	Exon 2 of 8	NP_001702.1	P21810

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BGN	ENST00000331595.9	TSL:1 MANE Select	c.238G>A	p.Gly80Ser	missense splice_region	Exon 2 of 8	ENSP00000327336.4	P21810
	BGN	ENST00000859737.1		c.238G>A	p.Gly80Ser	missense splice_region	Exon 2 of 8	ENSP00000529796.1
	BGN	ENST00000859739.1		c.238G>A	p.Gly80Ser	missense splice_region	Exon 2 of 8	ENSP00000529798.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Meester-Loeys syndrome (1)
-	1	-	not provided (1)
1	-	-	X-linked spondyloepimetaphyseal dysplasia;C4310811:Meester-Loeys syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.3	L
PhyloP100		4.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.048	D
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886037825;

hg19: chrX-152770327;