rs193302872

Positions:

• chr17-1775110-C-G

Variant summary

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

The NM_002615.7(SERPINF1):​c.696C>G​(p.Tyr232Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINF1 NM_002615.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 1.31

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-1775110-C-G is Pathogenic according to our data. Variant chr17-1775110-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 31851.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINF1	NM_002615.7	c.696C>G	p.Tyr232Ter	stop_gained	6/8	ENST00000254722.9	NP_002606.3
SERPINF1	NM_001329903.2	c.696C>G	p.Tyr232Ter	stop_gained	6/8		NP_001316832.1
SERPINF1	NM_001329904.2	c.135C>G	p.Tyr45Ter	stop_gained	5/7		NP_001316833.1
SERPINF1	NM_001329905.2	c.135C>G	p.Tyr45Ter	stop_gained	2/4		NP_001316834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9	c.696C>G	p.Tyr232Ter	stop_gained	6/8	1	NM_002615.7	ENSP00000254722	P1
SERPINF1	ENST00000573763.1	c.90C>G	p.Tyr30Ter	stop_gained	2/4	3		ENSP00000461405
SERPINF1	ENST00000572048.1	c.135C>G	p.Tyr45Ter	stop_gained	2/3	2		ENSP00000458484
SERPINF1	ENST00000576406.5	c.135C>G	p.Tyr45Ter	stop_gained	5/6	3		ENSP00000461214

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 11, 2011

- -

not provided Other:1

not provided, no classification provided

curation

Osteogenesis Imperfecta Variant Database (SERPINF1)

Mar 02, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.73	D
MutationTaster	Benign	1.0	A;A
Vest4		0.76
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs193302872; hg19: chr17-1678404;