4-87845066-GGAAA-G

Variant names:

• chr4-87845066-GGAAA-G
• rs753138805
• NM_020203.6:c.209_212delAAGA

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.Lys70IlefsTer26) 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
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.85

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]

ACMG classification

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 rank	MANE	Protein	UniProt
MEPE	NM_020203.6	c.209_212delAAGA	p.Lys70IlefsTer26	frameshift_variant	Exon 4 of 4	ENST00000361056.4	NP_064588.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEPE	ENST00000361056.4	c.209_212delAAGA	p.Lys70IlefsTer26	frameshift_variant	Exon 4 of 4	1	NM_020203.6	ENSP00000354341.3

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152076 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00104 AC XY: 141 AN XY: 135360

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.: 0 AF XY: 0.000669 AC XY: 486 AN XY: 726878

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: 89 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74406

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.: 0

Bravo AF: 0.000487

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000601

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

MEPE-related disorder Uncertain:1

Sep 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

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

Other links and lift over

dbSNP: rs753138805; hg19: chr4-88766218;