17-1766987-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_002615.7(SERPINF1):c.77C>G(p.Pro26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,553,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P26P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: SERPINF1 NM_002615.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.01

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07170451).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000514 (72/1401676) while in subpopulation MID AF= 0.000732 (4/5462). AF 95% confidence interval is 0.000336. There are 0 homozygotes in gnomad4_exome. There are 52 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINF1	NM_002615.7	c.77C>G	p.Pro26Arg	missense_variant	2/8	ENST00000254722.9
SERPINF1	NM_001329903.2	c.77C>G	p.Pro26Arg	missense_variant	2/8
SERPINF1	NM_001329904.2	c.-477-2865C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINF1	ENST00000254722.9	c.77C>G	p.Pro26Arg	missense_variant	2/8	1	NM_002615.7	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000888 AC: 14 AN: 157656 Hom.: 0 AF XY: 0.000156 AC XY: 13 AN XY: 83360

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000327

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000514 AC: 72 AN: 1401676 Hom.: 0 Cov.: 30 AF XY: 0.0000752 AC XY: 52 AN XY: 691564

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000453

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000259

Gnomad4 OTH exome AF: 0.0000689

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.000103 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SERPINF1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The SERPINF1 c.77C>G variant is predicted to result in the amino acid substitution p.Pro26Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.052% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	0.46
Dann	Uncertain	0.98
DEOGEN2	Benign	0.062	T;T;T;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.46	T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.072	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.070	N;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.069	T;.;.;.;.
Sift4G	Benign	0.19	T;D;T;T;T
Polyphen		0.087	B;.;.;.;.
Vest4		0.16
MutPred		0.23		Loss of glycosylation at P26 (P = 0.034);Loss of glycosylation at P26 (P = 0.034);Loss of glycosylation at P26 (P = 0.034);Loss of glycosylation at P26 (P = 0.034);Loss of glycosylation at P26 (P = 0.034);
MVP		0.64
MPC		0.075
ClinPred		0.029	T
GERP RS		-4.4
Varity_R		0.057
gMVP		0.29

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: rs997267726; hg19: chr17-1670281;