rs2070933

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-153506075-C-G
• chrX-153506075-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS2_Supporting

The NM_001711.6(BGN):​c.564C>G​(p.Ile188Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,095,343 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I188I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: BGN NM_001711.6 missense, splice_region
• Scores: Splicing: ADA: 0.0006858
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.15
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3011409).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AD geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BGN	NM_001711.6	c.564C>G	p.Ile188Met	missense_variant, splice_region_variant	Exon 4 of 8	ENST00000331595.9	NP_001702.1
BGN	XM_017029724.3	c.564C>G	p.Ile188Met	missense_variant, splice_region_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>G	p.Ile188Met	missense_variant, splice_region_variant	Exon 4 of 8	1	NM_001711.6	ENSP00000327336.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1095343 Hom.: 0 Cov.: 32 AF XY: 0.00000554 AC XY: 2 AN XY: 360915

African (AFR) AF: 0.00 AC: 0 AN: 26357

American (AMR) AF: 0.00 AC: 0 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.00 AC: 0 AN: 54064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840058

Other (OTH) AF: 0.00 AC: 0 AN: 46018

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	0.66
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	0.078	D
MutationAssessor	Benign	1.3	L;.
PhyloP100		-3.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.76	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.13	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.89	P;.
Vest4		0.47
MutPred		0.70		Gain of disorder (P = 0.018);.;
MVP		0.91
MPC		0.48
ClinPred		0.76	D
GERP RS		-9.3
Varity_R		0.33
gMVP		0.43
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00069
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.13		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;