X-153506075-C-T

Variant names:

• chrX-153506075-C-T
• rs2070933
• NM_001711.6:c.564C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001711.6(BGN):​c.564C>T​(p.Ile188Ile) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,207,610 control chromosomes in the GnomAD database, including 286 homozygotes. There are 6,479 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (99 hom., 1075 hem., cov: 23)
  • Exomes 𝑓: 0.015 (187 hom. 5404 hem.)
• Consequence: BGN NM_001711.6 splice_region, synonymous
• Scores: Splicing: ADA: 0.001369
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.15
• Publications: 8 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: Ambry Genetics, Genomics England PanelApp, Illumina, G2P
• X-linked spondyloepimetaphyseal dysplasia

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant X-153506075-C-T is Benign according to our data. Variant chrX-153506075-C-T is described in ClinVar as Benign. ClinVar VariationId is 1167739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BGN	NM_001711.6	c.564C>T	p.Ile188Ile	splice_region_variant, synonymous_variant	Exon 4 of 8	ENST00000331595.9	NP_001702.1
BGN	XM_017029724.3	c.564C>T	p.Ile188Ile	splice_region_variant, synonymous_variant	Exon 3 of 7		XP_016885213.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BGN	ENST00000331595.9	c.564C>T	p.Ile188Ile	splice_region_variant, synonymous_variant	Exon 4 of 8	1	NM_001711.6	ENSP00000327336.4

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 3809 AN: 112234 Hom.: 98 Cov.: 23

Gnomad AFR AF: 0.0789

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0557

Gnomad EAS AF: 0.0777

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.0364

GnomAD2 exomes AF: 0.0235 AC: 4272 AN: 181513 AF XY: 0.0200

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.00647

Gnomad ASJ exome AF: 0.0556

Gnomad EAS exome AF: 0.0896

Gnomad FIN exome AF: 0.00659

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0155 AC: 16939 AN: 1095322 Hom.: 187 Cov.: 32 AF XY: 0.0150 AC XY: 5404 AN XY: 360902

African (AFR) AF: 0.0848 AC: 2235 AN: 26355

American (AMR) AF: 0.00745 AC: 262 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.0555 AC: 1074 AN: 19367

East Asian (EAS) AF: 0.0756 AC: 2283 AN: 30179

South Asian (SAS) AF: 0.00880 AC: 476 AN: 54064

European-Finnish (FIN) AF: 0.00755 AC: 302 AN: 39984

Middle Eastern (MID) AF: 0.0172 AC: 71 AN: 4129

European-Non Finnish (NFE) AF: 0.0110 AC: 9252 AN: 840043

Other (OTH) AF: 0.0214 AC: 984 AN: 46018

GnomAD4 genome AF: 0.0340 AC: 3818 AN: 112288 Hom.: 99 Cov.: 23 AF XY: 0.0312 AC XY: 1075 AN XY: 34464

African (AFR) AF: 0.0790 AC: 2439 AN: 30870

American (AMR) AF: 0.0190 AC: 203 AN: 10709

Ashkenazi Jewish (ASJ) AF: 0.0557 AC: 148 AN: 2655

East Asian (EAS) AF: 0.0777 AC: 276 AN: 3553

South Asian (SAS) AF: 0.0116 AC: 31 AN: 2670

European-Finnish (FIN) AF: 0.00583 AC: 36 AN: 6174

Middle Eastern (MID) AF: 0.0137 AC: 3 AN: 219

European-Non Finnish (NFE) AF: 0.0118 AC: 627 AN: 53226

Other (OTH) AF: 0.0360 AC: 55 AN: 1528

Alfa AF: 0.0232 Hom.: 1159

Bravo AF: 0.0377

EpiCase AF: 0.0123

EpiControl AF: 0.0124

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 30, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.22
DANN	Benign	0.78
PhyloP100		-3.2
Mutation Taster		=77/23	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2070933; hg19: chrX-152771533; COSMIC: COSV59037073;