rs1800247

Variant names:

• chr1-156242034-T-C
• rs1800247
• ENST00000490491.5:c.565-519T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001199661.1(PMF1-BGLAP):​c.504-519T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 621,846 control chromosomes in the GnomAD database, including 14,334 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3273 hom., cov: 32)
  • Exomes 𝑓: 0.21 (11061 hom.)
• Consequence: PMF1-BGLAP NM_001199661.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140
• Publications: 34 publications found

Genes affected

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: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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199661.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMF1-BGLAP	NM_001199661.1		c.504-519T>C		intron	N/A	NP_001186590.1	Q6P1K2-5
	PMF1-BGLAP	NM_001199662.1		c.565-519T>C		intron	N/A	NP_001186591.1	U3KQ54
	PMF1-BGLAP	NM_001199663.1		c.369-519T>C		intron	N/A	NP_001186592.1	Q6P1K2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMF1-BGLAP	ENST00000490491.5	TSL:2	c.565-519T>C		intron	N/A	ENSP00000475561.1	U3KQ54
	PMF1-BGLAP	ENST00000320139.5	TSL:1	c.369-519T>C		intron	N/A	ENSP00000324909.5
	PMF1-BGLAP	ENST00000368276.8	TSL:3	c.504-519T>C		intron	N/A	ENSP00000357259.4

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31290 AN: 151796 Hom.: 3273 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.213 AC: 99983 AN: 469930 Hom.: 11061 Cov.: 5 AF XY: 0.215 AC XY: 52566 AN XY: 244664

African (AFR) AF: 0.197 AC: 2543 AN: 12920

American (AMR) AF: 0.185 AC: 3456 AN: 18646

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 3011 AN: 13510

East Asian (EAS) AF: 0.239 AC: 7401 AN: 30902

South Asian (SAS) AF: 0.237 AC: 10165 AN: 42892

European-Finnish (FIN) AF: 0.153 AC: 4500 AN: 29402

Middle Eastern (MID) AF: 0.248 AC: 487 AN: 1960

European-Non Finnish (NFE) AF: 0.214 AC: 62689 AN: 293410

Other (OTH) AF: 0.218 AC: 5731 AN: 26288

GnomAD4 genome AF: 0.206 AC: 31286 AN: 151916 Hom.: 3273 Cov.: 32 AF XY: 0.202 AC XY: 15005 AN XY: 74248

African (AFR) AF: 0.194 AC: 8024 AN: 41450

American (AMR) AF: 0.207 AC: 3169 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 754 AN: 3464

East Asian (EAS) AF: 0.284 AC: 1444 AN: 5084

South Asian (SAS) AF: 0.244 AC: 1171 AN: 4802

European-Finnish (FIN) AF: 0.147 AC: 1559 AN: 10596

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14480 AN: 67926

Other (OTH) AF: 0.220 AC: 464 AN: 2110

Alfa AF: 0.216 Hom.: 5265

Bravo AF: 0.211

Asia WGS AF: 0.249 AC: 865 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.8
DANN	Benign	0.57
PhyloP100		-0.14
PromoterAI		-0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800247; hg19: chr1-156211825; COSMIC: COSV52744978; COSMIC: COSV52744978;