Variant 4-87845066-GGAAA-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020203.6(MEPE):c.209_212delAAGA(p.Lys70fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000658 in 1,613,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

MEPE
NM_020203.6 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.85

Variant links:

Genes affected

MEPE (HGNC:13361): (matrix extracellular phosphoglycoprotein) This gene encodes a secreted calcium-binding phosphoprotein that belongs to the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family of proteins. Members of this family are components of the extracellular matrix of bone and dentin and regulate bone mineralization. Deficiency of a similar protein in mouse results in increased bone mass. Mice lacking this gene are resistant to aging-related trabecular bone loss. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

MEPE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEPE	NM_020203.6 linkuse as main transcript	c.209_212delAAGA	p.Lys70fs	frameshift_variant	4/4	ENST00000361056.4	NP_064588.1	Q9NQ76-1A0A024RDD1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEPE	ENST00000361056.4 linkuse as main transcript	c.209_212delAAGA	p.Lys70fs	frameshift_variant	4/4	1	NM_020203.6	ENSP00000354341.3		Q9NQ76-1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000969

AC:

242

AN:

249848

Hom.:

AF XY:

0.00104

AC XY:

141

AN XY:

135360

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00287

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000665

AC:

972

AN:

1461196

Hom.:

AF XY:

0.000669

AC XY:

486

AN XY:

726878

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00249

Gnomad4 NFE exome

AF:

0.000718

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000585

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00236

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000327

Hom.:

Bravo

AF:

0.000487

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000601

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MEPE-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The MEPE c.302_305delAAGA variant is predicted to result in a frameshift and premature protein termination (p.Lys101Ilefs*26). This variant has been reported in the heterozygous state in multiple affected and unaffected individuals from two families with otosclerosis and also been reported in unrelated nine patients and one unaffected individual in an otosclerosis case-control study (referred to as c.199_202delGAAA, Schrauwen et al. 2019. PubMed ID: 30287925). It has been associated with an increased risk of decreased bone mineral density (reported as p.Lys70IlefsTer26 or rs753138805 in Table S1, Surakka et al. 2020. PubMed ID: 33097703). This variant is reported in 0.29% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over