X-153504699-G-C

Variant summary

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

The NM_001711.6(BGN):c.68G>C(p.Gly23Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,929 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: BGN NM_001711.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.847

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=0.18943512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BGN	NM_001711.6	c.68G>C	p.Gly23Ala	missense_variant	2/8	ENST00000331595.9
BGN	XM_017029724.3	c.68G>C	p.Gly23Ala	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BGN	ENST00000331595.9	c.68G>C	p.Gly23Ala	missense_variant	2/8	1	NM_001711.6	P1
BGN	ENST00000431891.1	c.68G>C	p.Gly23Ala	missense_variant	2/5	5
BGN	ENST00000472615.5	n.212G>C		non_coding_transcript_exon_variant	2/8	5
BGN	ENST00000480756.1	n.210G>C		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183243 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097929 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363369

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000165 AC: 2

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

Aug 08, 2020

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 output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with BGN-related conditions. This variant is present in population databases (rs782728797, ExAC 0.02%). This sequence change replaces glycine with alanine at codon 23 of the BGN protein (p.Gly23Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;T
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.10
Sift	Benign	0.085	T;D
Sift4G	Benign	0.19	T;T
Polyphen		0.18	B;.
Vest4		0.12
MutPred		0.51		Gain of catalytic residue at G23 (P = 0.0556);Gain of catalytic residue at G23 (P = 0.0556);
MVP		0.78
MPC		0.37
ClinPred		0.25	T
GERP RS		3.9
Varity_R		0.34
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782728797; hg19: chrX-152770157;