rs398122520

Positions:

• chr17-1775066-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002615.7(SERPINF1):​c.653del​(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:4
• Conservation: PhyloP100: 0.338

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 41894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1775066-GT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINF1	NM_002615.7	c.653del	p.Val218GlufsTer22	frameshift_variant	6/8	ENST00000254722.9
SERPINF1	NM_001329903.2	c.653del	p.Val218GlufsTer22	frameshift_variant	6/8
SERPINF1	NM_001329904.2	c.92del	p.Val31GlufsTer22	frameshift_variant	5/7
SERPINF1	NM_001329905.2	c.92del	p.Val31GlufsTer22	frameshift_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF1	ENST00000254722.9	c.653del	p.Val218GlufsTer22	frameshift_variant	6/8	1	NM_002615.7	P1
SERPINF1	ENST00000573763.1	c.47del	p.Val16GlufsTer22	frameshift_variant	2/4	3
SERPINF1	ENST00000572048.1	c.92del	p.Val31GlufsTer22	frameshift_variant	2/3	2
SERPINF1	ENST00000576406.5	c.92del	p.Val31GlufsTer22	frameshift_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 04, 2023	This sequence change creates a premature translational stop signal (p.Val218Glufs*22) in the SERPINF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SERPINF1 are known to be pathogenic (PMID: 21353196, 21826736). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with osteogenesis imperfecta (PMID: 23054245, 29620724). ClinVar contains an entry for this variant (Variation ID: 41894). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2017	- -

Osteogenesis imperfecta type 6 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Apr 20, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2012	- -

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: rs398122520; hg19: chr17-1678360;