rs879255604

chrX-153505950-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP5 BP4

The NM_001711.6(BGN):c.439A>G(p.Lys147Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K147N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: BGN NM_001711.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0230

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-153505952-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1723874.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant X-153505950-A-G is Pathogenic according to our data. Variant chrX-153505950-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 243090.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2484926).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BGN	NM_001711.6	c.439A>G	p.Lys147Glu	missense_variant	4/8	ENST00000331595.9
BGN	XM_017029724.3	c.439A>G	p.Lys147Glu	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BGN	ENST00000331595.9	c.439A>G	p.Lys147Glu	missense_variant	4/8	1	NM_001711.6	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked spondyloepimetaphyseal dysplasia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.20	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.25
Sift	Benign	0.21	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.89	P;.
Vest4		0.81
MutPred		0.46		Loss of methylation at K147 (P = 0.0177);.;
MVP		0.73
MPC		0.89
ClinPred		0.85	D
GERP RS		4.7
Varity_R		0.47
gMVP		0.56

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: rs879255604; hg19: chrX-152771408;