1-156243140-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_199173.6(BGLAP):c.281G>A(p.Arg94Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,022 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (45 hom.)
• Consequence: BGLAP NM_199173.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0770

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:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047871172).
• BP6: Variant 1-156243140-G-A is Benign according to our data. Variant chr1-156243140-G-A is described in ClinVar as [Benign]. Clinvar id is 780264.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2050/152250) while in subpopulation AFR AF= 0.0467 (1940/41540). AF 95% confidence interval is 0.045. There are 48 homozygotes in gnomad4. There are 941 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2049 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BGLAP	NM_199173.6	c.281G>A	p.Arg94Gln	missense_variant	4/4	ENST00000368272.5
PMF1-BGLAP	NM_001199662.1	c.*145G>A		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BGLAP	ENST00000368272.5	c.281G>A	p.Arg94Gln	missense_variant	4/4	1	NM_199173.6	P1
BGLAP	ENST00000471413.1	n.782G>A		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2049 AN: 152132 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00355 AC: 892 AN: 251364 Hom.: 22 AF XY: 0.00262 AC XY: 356 AN XY: 135870

Gnomad AFR exome AF: 0.0474

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00137 AC: 1997 AN: 1461772 Hom.: 45 Cov.: 32 AF XY: 0.00114 AC XY: 831 AN XY: 727200

Gnomad4 AFR exome AF: 0.0477

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.0135 AC: 2050 AN: 152250 Hom.: 48 Cov.: 32 AF XY: 0.0126 AC XY: 941 AN XY: 74446

Gnomad4 AFR AF: 0.0467

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00260 Hom.: 18

Bravo AF: 0.0153

ESP6500AA AF: 0.0493 AC: 217

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00427 AC: 518

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	8.6
Dann	Uncertain	0.99
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0048	T
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	0.61	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.19
Sift	Benign	0.33	T
Sift4G	Benign	0.25	T
Polyphen		0.026	B
Vest4		0.12
MVP		0.54
MPC		0.30
ClinPred		0.0074	T
GERP RS		-1.7
Varity_R		0.027
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34702397; hg19: chr1-156212931; COSMIC: COSV99047002; COSMIC: COSV99047002;