rs6828

chr17-1776708-T-Achr17-1776708-T-Cchr17-1776708-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_002615.7(SERPINF1):c.963T>A(p.Tyr321Ter) 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

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 Likely_pathogenic. Variant got 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 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINF1	NM_002615.7	c.963T>A	p.Tyr321Ter	stop_gained	7/8	ENST00000254722.9
SERPINF1	NM_001329903.2	c.963T>A	p.Tyr321Ter	stop_gained	7/8
SERPINF1	NM_001329904.2	c.402T>A	p.Tyr134Ter	stop_gained	6/7
SERPINF1	NM_001329905.2	c.402T>A	p.Tyr134Ter	stop_gained	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF1	ENST00000254722.9	c.963T>A	p.Tyr321Ter	stop_gained	7/8	1	NM_002615.7	P1
SERPINF1	ENST00000573763.1	c.357T>A	p.Tyr119Ter	stop_gained	3/4	3
SERPINF1	ENST00000572517.1	n.259T>A		non_coding_transcript_exon_variant	1/2	2

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
Eigen	Benign	-0.73
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.26	N
MutationTaster	Benign	1.9e-21	P;P
Vest4		0.92
GERP RS		-8.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs6828; hg19: chr17-1680002;