chr15-80979291-CTT-C

Variant names:

• chr15-80979291-CTT-C
• rs745891632
• NM_015154.3:c.631_632delAA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_015154.3(MESD):​c.631_632delAA​(p.Lys211GlufsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MESD NM_015154.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.30

Genes affected

MESD (HGNC:13520): (mesoderm development LRP chaperone) Predicted to enable low-density lipoprotein particle receptor binding activity. Involved in ossification and protein folding. Located in endoplasmic reticulum. Implicated in osteogenesis imperfecta type 20. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-80979291-CTT-C is Pathogenic according to our data. Variant chr15-80979291-CTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 692264.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-80979291-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MESD	NM_015154.3	c.631_632delAA	p.Lys211GlufsTer19	frameshift_variant	Exon 3 of 3	ENST00000261758.6	NP_055969.1
MESD	NR_126327.2	n.659_660delAA		non_coding_transcript_exon_variant	Exon 3 of 5
MESD	NR_126328.2	n.241+10286_241+10287delAA		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MESD	ENST00000261758.6	c.631_632delAA	p.Lys211GlufsTer19	frameshift_variant	Exon 3 of 3	1	NM_015154.3	ENSP00000261758.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta, type 20 Pathogenic:2

Aug 27, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported to be associated with MESD related disorder (ClinVar ID: VCV000692264 /PMID: 31564437). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Oct 25, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: rs745891632; hg19: chr15-81271632;