chrX-153504648-G-A

Position:

chrX-153504648-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The ENST00000331595.9(BGN):c.17G>A(p.Arg6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,205,382 control chromosomes in the GnomAD database, including 1 homozygotes. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. R6C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000021 ( 1 hom. 4 hem. )

Consequence

BGN
ENST00000331595.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.00500

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12144002).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000211 (23/1092600) while in subpopulation AMR AF= 0.000143 (5/34976). AF 95% confidence interval is 0.0000555. There are 1 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BGN	NM_001711.6 linkuse as main transcript	c.17G>A	p.Arg6His	missense_variant	2/8	ENST00000331595.9	NP_001702.1
BGN	XM_017029724.3 linkuse as main transcript	c.17G>A	p.Arg6His	missense_variant	1/7		XP_016885213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
BGN	ENST00000331595.9 linkuse as main transcript	c.17G>A	p.Arg6His	missense_variant	2/8	1	NM_001711.6	ENSP00000327336	P1
BGN	ENST00000431891.1 linkuse as main transcript	c.17G>A	p.Arg6His	missense_variant	2/5	5		ENSP00000402525
BGN	ENST00000472615.5 linkuse as main transcript	n.161G>A		non_coding_transcript_exon_variant	2/8	5
BGN	ENST00000480756.1 linkuse as main transcript	n.159G>A		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112782

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34944

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000223

AC:

AN:

179680

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

64614

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000370

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000539

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000249

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000211

AC:

AN:

1092600

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

358908

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

Gnomad4 AMR exome

AF:

0.000143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000333

Gnomad4 SAS exome

AF:

0.0000557

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000143

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112782

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34944

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked spondyloepimetaphyseal dysplasia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 10, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 6 of the BGN protein (p.Arg6His). This variant is present in population databases (rs781931209, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with BGN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1033440). 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 tolerated. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The p.R6H variant (also known as c.17G>A), located in coding exon 1 of the BGN gene, results from a G to A substitution at nucleotide position 17. The arginine at codon 6 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.48

DANN

Benign

0.96

DEOGEN2

Benign

0.097

T;T

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.37

N;N

REVEL

Benign

0.10

Sift

Uncertain

0.029

D;D

Sift4G

Benign

0.12

T;T

Polyphen

0.73

P;.

Vest4

0.049

MutPred

0.49

Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);

MVP

0.68

MPC

0.40

ClinPred

0.052

GERP RS

0.73

Varity_R

0.043

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over