17-1766987-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_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. 16/23 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -1.01

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07170451).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 52 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINF1	NM_002615.7 link	c.77C>G	p.Pro26Arg	missense_variant	Exon 2 of 8	ENST00000254722.9	NP_002606.3	P36955A0A140VKF3
SERPINF1	NM_001329903.2 link	c.77C>G	p.Pro26Arg	missense_variant	Exon 2 of 8		NP_001316832.1	P36955A0A140VKF3
SERPINF1	NM_001329904.2 link	c.-477-2865C>G		intron_variant	Intron 1 of 6		NP_001316833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9 link	c.77C>G	p.Pro26Arg	missense_variant	Exon 2 of 8	1	NM_002615.7	ENSP00000254722.4		P36955

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000888

AC:

AN:

157656

AF XY:

0.000156

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000327

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000514

AC:

AN:

1401676

Hom.:

Cov.:

AF XY:

0.0000752

AC XY:

AN XY:

691564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

31818

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35998

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25182

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

36144

Gnomad4 SAS exome

AF:

0.000453

AC:

AN:

79388

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

49268

Gnomad4 NFE exome

AF:

0.0000259

AC:

AN:

1080354

Gnomad4 Remaining exome

AF:

0.0000689

AC:

AN:

58062

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.0000394

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

AC:

0.0000241394

AN:

0.0000241394

Gnomad4 AMR

AF:

0.0000654

AC:

0.000065445

AN:

0.000065445

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000588

AC:

0.0000588045

AN:

0.0000588045

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000103

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

SERPINF1-related disorder

Uncertain:1

Feb 21, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.27

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

LIST_S2

Benign

0.46

T;T;T;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.072

T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.4

L;.;.;.;.

PrimateAI

Benign

0.34

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

GERP RS

-4.4

Varity_R

0.057

gMVP

0.29

Mutation Taster

=98/2

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over