rs869312908

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_002615.7(SERPINF1):c.1152_1170delCCCGCTGGACTATCACCTT(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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F384F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPINF1
NM_002615.7 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.83

Publications

1 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
osteogenesis imperfecta type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta type 4
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SERPINF1 links:

ENSG00000295186 (HGNC:):

ENSG00000295186 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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 0.0835 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PP5

Variant 17-1777333-CTCACCTTCCCGCTGGACTA-C is Pathogenic according to our data. Variant chr17-1777333-CTCACCTTCCCGCTGGACTA-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 224879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINF1	NM_002615.7 link	c.1152_1170delCCCGCTGGACTATCACCTT	p.Phe384LeufsTer9	frameshift_variant	Exon 8 of 8	ENST00000254722.9	NP_002606.3	P36955A0A140VKF3
SERPINF1	NM_001329903.2 link	c.1152_1170delCCCGCTGGACTATCACCTT	p.Phe384LeufsTer9	frameshift_variant	Exon 8 of 8		NP_001316832.1	P36955A0A140VKF3
SERPINF1	NM_001329904.2 link	c.591_609delCCCGCTGGACTATCACCTT	p.Phe197LeufsTer9	frameshift_variant	Exon 7 of 7		NP_001316833.1
SERPINF1	NM_001329905.2 link	c.591_609delCCCGCTGGACTATCACCTT	p.Phe197LeufsTer9	frameshift_variant	Exon 4 of 4		NP_001316834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINF1	ENST00000254722.9 link	c.1152_1170delCCCGCTGGACTATCACCTT	p.Phe384LeufsTer9	frameshift_variant	Exon 8 of 8	1	NM_002615.7	ENSP00000254722.4	P36955
SERPINF1	ENST00000572517.1 link	n.448_466delCCCGCTGGACTATCACCTT		non_coding_transcript_exon_variant	Exon 2 of 2	2
ENSG00000295186	ENST00000728537.1 link	n.77-861_77-843delCCCGCTGGACTATCACCTT		intron_variant	Intron 1 of 1
SERPINF1	ENST00000573763.1 link	c.125_143delTCACCTTCCCGCTGGACTA		downstream_gene_variant		3		ENSP00000461405.1	I3L4N7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.8

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over