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GeneBe

1-156243120-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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. 13/20 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

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.26
Variant links:
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]

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ACMG classification

Classification made for transcript

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/exons MANE UniProt
BGLAPNM_199173.6 linkuse as main transcriptc.261C>G p.Ile87Met missense_variant 4/4 ENST00000368272.5
PMF1-BGLAPNM_001199662.1 linkuse as main transcriptc.*125C>G 3_prime_UTR_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BGLAPENST00000368272.5 linkuse as main transcriptc.261C>G p.Ile87Met missense_variant 4/41 NM_199173.6 P1
BGLAPENST00000471413.1 linkuse as main transcriptn.762C>G non_coding_transcript_exon_variant 2/25

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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 21, 2023The 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
MutationTaster
Benign
1.0
N
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; API