1-156243120-C-G

Variant names:

• chr1-156243120-C-G
• NM_199173.6:c.261C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_199173.6(BGLAP):​c.261C>G​(p.Ile87Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BGLAP NM_199173.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.26

Genes affected

BGLAP (HGNC:1043): (bone gamma-carboxyglutamate protein) This gene encodes a highly abundant bone protein secreted by osteoblasts that regulates bone remodeling and energy metabolism. The encoded protein contains a Gla (gamma carboxyglutamate) domain, which functions in binding to calcium and hydroxyapatite, the mineral component of bone. Serum osteocalcin levels may be negatively correlated with metabolic syndrome. Read-through transcription exists between this gene and the neighboring upstream gene, PMF1 (polyamine-modulated factor 1), but the encoded protein only shows sequence identity with the upstream gene product. [provided by RefSeq, Jun 2015]

PMF1-BGLAP (HGNC:42953): (PMF1-BGLAP readthrough) This locus represents naturally occurring read-through transcription between the neighboring PMF1 (polyamine-modulated factor 1) and BGLAP (bone gamma-carboxyglutamate Gla protein) genes on chromosome 1. Alternative splicing results in multiple transcript variants encoding isoforms that share sequence identity with the upstream gene product, but they contain distinct C-termini due to frameshifts versus the downstream gene coding sequence. [provided by RefSeq, Dec 2010]

PAQR6 (HGNC:30132): (progestin and adipoQ receptor family member 6) Predicted to enable signaling receptor activity. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30630207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BGLAP	NM_199173.6	c.261C>G	p.Ile87Met	missense_variant	Exon 4 of 4	ENST00000368272.5	NP_954642.1
PAQR6	NM_198406.3	c.*1009G>C		downstream_gene_variant		ENST00000292291.10	NP_940798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BGLAP	ENST00000368272.5	c.261C>G	p.Ile87Met	missense_variant	Exon 4 of 4	1	NM_199173.6	ENSP00000357255.4
PMF1-BGLAP	ENST00000490491.5	c.*125C>G		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000475561.1
PAQR6	ENST00000292291.10	c.*1009G>C		downstream_gene_variant		1	NM_198406.3	ENSP00000292291.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.261C>G (p.I87M) alteration is located in exon 4 (coding exon 4) of the BGLAP gene. This alteration results from a C to G substitution at nucleotide position 261, causing the isoleucine (I) at amino acid position 87 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	5.1
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.45
Sift	Benign	0.046	D
Sift4G	Benign	0.076	T
Polyphen		0.98	D
Vest4		0.25
MutPred		0.51		Gain of disorder (P = 0.0349);
MVP		0.56
MPC		0.35
ClinPred		0.19	T
GERP RS		-6.2
Varity_R		0.084
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156212911;