rs869312908

chr17-1777333-CTCACCTTCCCGCTGGACTA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_002615.7(SERPINF1):c.1152_1170del(p.Phe384LeufsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINF1 NM_002615.7 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.83

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 12 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 0.0891 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-1777333-CTCACCTTCCCGCTGGACTA-C is Pathogenic according to our data. Variant chr17-1777333-CTCACCTTCCCGCTGGACTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 224879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1777333-CTCACCTTCCCGCTGGACTA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINF1	NM_002615.7	c.1152_1170del	p.Phe384LeufsTer9	frameshift_variant	8/8	ENST00000254722.9
SERPINF1	NM_001329903.2	c.1152_1170del	p.Phe384LeufsTer9	frameshift_variant	8/8
SERPINF1	NM_001329904.2	c.591_609del	p.Phe197LeufsTer9	frameshift_variant	7/7
SERPINF1	NM_001329905.2	c.591_609del	p.Phe197LeufsTer9	frameshift_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF1	ENST00000254722.9	c.1152_1170del	p.Phe384LeufsTer9	frameshift_variant	8/8	1	NM_002615.7	P1
SERPINF1	ENST00000572517.1	n.448_466del		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 05, 2023

This sequence change creates a premature translational stop signal (p.Phe384Leufs*9) in the SERPINF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the SERPINF1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with osteogenesis imperfecta type VI (PMID: 25565926). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224879). For these reasons, this variant has been classified as Pathogenic. -

Osteogenesis imperfecta type 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312908; hg19: chr17-1680627;