chr15-80979291-CTT-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 6 publications found

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]

MESD Gene-Disease associations (from GenCC):

• osteogenesis imperfecta, type 20

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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. Fraction of 0.105 CDS is truncated, and there are 3 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 VariationId is 692264.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015154.3. 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
	MESD	NM_015154.3	MANE Select	c.631_632delAA	p.Lys211GlufsTer19	frameshift	Exon 3 of 3	NP_055969.1	Q14696-1
	MESD	NR_126327.2		n.659_660delAA		non_coding_transcript_exon	Exon 3 of 5
	MESD	NR_126328.2		n.241+10286_241+10287delAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MESD	ENST00000261758.6	TSL:1 MANE Select	c.631_632delAA	p.Lys211GlufsTer19	frameshift	Exon 3 of 3	ENSP00000261758.4	Q14696-1
	MESD	ENST00000561312.5	TSL:1	c.631_632delAA	p.Lys211GlufsTer19	frameshift	Exon 3 of 5	ENSP00000453430.1	Q14696-1
	MESD	ENST00000619987.4	TSL:1	n.631_632delAA		non_coding_transcript_exon	Exon 3 of 5	ENSP00000482455.1	Q14696-1

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Osteogenesis imperfecta, type 20 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=13/187	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs745891632; hg19: chr15-81271632;