X-153504721-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001711.6(BGN):c.90C>G(p.Asp30Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: BGN NM_001711.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -3.03

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12104723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BGN	NM_001711.6	c.90C>G	p.Asp30Glu	missense_variant	2/8	ENST00000331595.9
BGN	XM_017029724.3	c.90C>G	p.Asp30Glu	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BGN	ENST00000331595.9	c.90C>G	p.Asp30Glu	missense_variant	2/8	1	NM_001711.6	P1
BGN	ENST00000431891.1	c.90C>G	p.Asp30Glu	missense_variant	2/5	5
BGN	ENST00000472615.5	n.234C>G		non_coding_transcript_exon_variant	2/8	5
BGN	ENST00000480756.1	n.232C>G		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BGN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2023

The BGN c.90C>G variant is predicted to result in the amino acid substitution p.Asp30Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 15, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 30 of the BGN protein (p.Asp30Glu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1490325). This variant has not been reported in the literature in individuals affected with BGN-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.029
Dann	Benign	0.90
DEOGEN2	Benign	0.13	T;T
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.42	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.80	T;T
Sift4G	Benign	0.98	T;T
Polyphen		1.0	D;.
Vest4		0.41
MutPred		0.38		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.88
MPC		1.0
ClinPred		0.22	T
GERP RS		-5.5
Varity_R		0.13
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs782549135; hg19: chrX-152770179;