X-153504722-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001711.6(BGN):c.91G>A(p.Asp31Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000638 in 1,097,887 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D31Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000064 (0 hom. 2 hem.)
• Consequence: BGN NM_001711.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.06

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_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3046366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BGN	NM_001711.6	c.91G>A	p.Asp31Asn	missense_variant	2/8	ENST00000331595.9
BGN	XM_017029724.3	c.91G>A	p.Asp31Asn	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BGN	ENST00000331595.9	c.91G>A	p.Asp31Asn	missense_variant	2/8	1	NM_001711.6	P1
BGN	ENST00000431891.1	c.91G>A	p.Asp31Asn	missense_variant	2/5	5
BGN	ENST00000472615.5	n.235G>A		non_coding_transcript_exon_variant	2/8	5
BGN	ENST00000480756.1	n.233G>A		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1097887 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363333

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 24, 2022

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 31 of the BGN protein (p.Asp31Asn). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.99	N;N
REVEL	Benign	0.13
Sift	Benign	0.033	D;D
Sift4G	Benign	0.28	T;T
Polyphen		0.0060	B;.
Vest4		0.37
MutPred		0.48		Gain of catalytic residue at D31 (P = 0.001);Gain of catalytic residue at D31 (P = 0.001);
MVP		0.94
MPC		0.39
ClinPred		0.75	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.57

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: rs1011782727; hg19: chrX-152770180;