1-156243037-C-T

Position:

• chr1-156243037-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_199173.6(BGLAP):​c.178C>T​(p.Pro60Ser) 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 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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: 1.50

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]

BGLAP (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a site Not hydroxylated (size 0) in uniprot entity OSTCN_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09595874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BGLAP	NM_199173.6	c.178C>T	p.Pro60Ser	missense_variant	4/4	ENST00000368272.5	NP_954642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BGLAP	ENST00000368272.5	c.178C>T	p.Pro60Ser	missense_variant	4/4	1	NM_199173.6	ENSP00000357255.4
PMF1-BGLAP	ENST00000490491.5	c.*42C>T		3_prime_UTR_variant	7/7	2		ENSP00000475561.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727202

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2023

The c.178C>T (p.P60S) alteration is located in exon 4 (coding exon 4) of the BGLAP gene. This alteration results from a C to T substitution at nucleotide position 178, causing the proline (P) at amino acid position 60 to be replaced by a serine (S). 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	0.077
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	1.0
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.36	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.096	T;T
MetaSVM	Uncertain	0.20	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.53	N;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.062	T;T
Vest4		0.32
MutPred		0.12		.;Loss of glycosylation at P161 (P = 0.0125);
MVP		0.30
MPC		0.30
ClinPred		0.81	D
GERP RS		2.9
gMVP		0.031

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr1-156212828;