rs398122520

Variant names:

• chr17-1775066-GT-G
• rs398122520
• NM_002615.7:c.653delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002615.7(SERPINF1):​c.653delT​(p.Val218GlufsTer22) 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPINF1 NM_002615.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.338
• Publications: 2 publications found

Genes affected

SERPINF1 (HGNC:8824): (serpin family F member 1) This gene encodes a member of the serpin family that does not display the serine protease inhibitory activity shown by many of the other serpin proteins. The encoded protein is secreted and strongly inhibits angiogenesis. In addition, this protein is a neurotrophic factor involved in neuronal differentiation in retinoblastoma cells. Mutations in this gene were found in individuals with osteogenesis imperfecta, type VI. [provided by RefSeq, Aug 2016]

SERPINF1 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 6

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-1775066-GT-G is Pathogenic according to our data. Variant chr17-1775066-GT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 41894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002615.7. 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
	SERPINF1	NM_002615.7	MANE Select	c.653delT	p.Val218GlufsTer22	frameshift	Exon 6 of 8	NP_002606.3
	SERPINF1	NM_001329903.2		c.653delT	p.Val218GlufsTer22	frameshift	Exon 6 of 8	NP_001316832.1	A0A140VKF3
	SERPINF1	NM_001329904.2		c.92delT	p.Val31GlufsTer22	frameshift	Exon 5 of 7	NP_001316833.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINF1	ENST00000254722.9	TSL:1 MANE Select	c.653delT	p.Val218GlufsTer22	frameshift	Exon 6 of 8	ENSP00000254722.4	P36955
	SERPINF1	ENST00000869424.1		c.653delT	p.Val218GlufsTer22	frameshift	Exon 6 of 8	ENSP00000539483.1
	SERPINF1	ENST00000869426.1		c.653delT	p.Val218GlufsTer22	frameshift	Exon 6 of 8	ENSP00000539485.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Osteogenesis imperfecta type 6 (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=0/200	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: rs398122520; hg19: chr17-1678360;