17-1766981-G-GC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002615.7(SERPINF1):c.77dup(p.Glu27GlyfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,403,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S24S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: SERPINF1 NM_002615.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.137

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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 27 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-1766981-G-GC is Pathogenic according to our data. Variant chr17-1766981-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 1342706.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINF1	NM_002615.7	c.77dup	p.Glu27GlyfsTer38	frameshift_variant	2/8	ENST00000254722.9
SERPINF1	NM_001329903.2	c.77dup	p.Glu27GlyfsTer38	frameshift_variant	2/8
SERPINF1	NM_001329904.2	c.-477-2865dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF1	ENST00000254722.9	c.77dup	p.Glu27GlyfsTer38	frameshift_variant	2/8	1	NM_002615.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000499 AC: 7 AN: 1403220 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 692532

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000275

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.00000370

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Sep 27, 2021

A heterozygous single base-pair duplication in exon 2 of the SERPINF1 gene that results in a frameshift and premature truncation of protein 38 amino acids downstream to codon 27 was detected. The observed variant c.77dup (p.Glu27GlyfsTer38) has not been reported in the 1000 genomes and gnomAD database. The variant has previously been reported in patients affected with osteogenesis imperfecta (Li et al. 2020). The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across primates. In summary, the variant meets our criteria to be classified as a pathogenic variant. -

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: rs1272920425; hg19: chr17-1670275;