17-1776708-T-A

Variant names:

• chr17-1776708-T-A
• rs6828
• NM_002615.7:c.963T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_002615.7(SERPINF1):​c.963T>A​(p.Tyr321*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y321Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 25)
• Consequence: SERPINF1 NM_002615.7 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.70
• Publications: 32 publications found

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

ENSG00000295186 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINF1	NM_002615.7	c.963T>A	p.Tyr321*	stop_gained	Exon 7 of 8	ENST00000254722.9	NP_002606.3
SERPINF1	NM_001329903.2	c.963T>A	p.Tyr321*	stop_gained	Exon 7 of 8		NP_001316832.1
SERPINF1	NM_001329904.2	c.402T>A	p.Tyr134*	stop_gained	Exon 6 of 7		NP_001316833.1
SERPINF1	NM_001329905.2	c.402T>A	p.Tyr134*	stop_gained	Exon 3 of 4		NP_001316834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9	c.963T>A	p.Tyr321*	stop_gained	Exon 7 of 8	1	NM_002615.7	ENSP00000254722.4

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.0	.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.0	.;.
MetaRNN	Benign	0.0	.;.
MutationAssessor	Benign	0.0	.;.
PhyloP100		-3.7
PROVEAN	Benign	0.0	.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.
Sift4G	Pathogenic	0.0	.;.
Vest4		0.92
GERP RS		-8.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=9/191	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs6828; hg19: chr17-1680002;