17-1769982-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002615.7(SERPINF1):c.215C>T(p.Thr72Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,613,816 control chromosomes in the GnomAD database, including 329,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.68 ( 36046 hom., cov: 32)

Exomes 𝑓: 0.63 ( 293400 hom. )

Consequence

SERPINF1
NM_002615.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.725

Publications

112 publications found

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 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

SERPINF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7483504E-6).

BP6

Variant 17-1769982-C-T is Benign according to our data. Variant chr17-1769982-C-T is described in ClinVar as Benign. ClinVar VariationId is 322000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SERPINF1	NM_002615.7 link	c.215C>T	p.Thr72Met	missense_variant	Exon 3 of 8	ENST00000254722.9	NP_002606.3
SERPINF1	NM_001329904.2 link	c.-347C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 7		NP_001316833.1
SERPINF1	NM_001329903.2 link	c.215C>T	p.Thr72Met	missense_variant	Exon 3 of 8		NP_001316832.1
SERPINF1	NM_001329904.2 link	c.-347C>T		5_prime_UTR_variant	Exon 2 of 7		NP_001316833.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINF1	ENST00000254722.9 link	c.215C>T	p.Thr72Met	missense_variant	Exon 3 of 8	1	NM_002615.7	ENSP00000254722.4

Frequencies

GnomAD3 genomes

AF:

0.679

AC:

103173

AN:

151970

Hom.:

35998

Cov.:

show subpopulations

Gnomad AFR

AF:

0.835

Gnomad AMI

AF:

0.709

Gnomad AMR

AF:

0.607

Gnomad ASJ

AF:

0.721

Gnomad EAS

AF:

0.523

Gnomad SAS

AF:

0.480

Gnomad FIN

AF:

0.550

Gnomad MID

AF:

0.693

Gnomad NFE

AF:

0.643

Gnomad OTH

AF:

0.702

GnomAD2 exomes

AF:

0.609

AC:

153242

AN:

251434

AF XY:

0.606

show subpopulations

Gnomad AFR exome

AF:

0.837

Gnomad AMR exome

AF:

0.517

Gnomad ASJ exome

AF:

0.723

Gnomad EAS exome

AF:

0.543

Gnomad FIN exome

AF:

0.548

Gnomad NFE exome

AF:

0.649

Gnomad OTH exome

AF:

0.631

GnomAD4 exome

AF:

0.630

AC:

920378

AN:

1461726

Hom.:

293400

Cov.:

AF XY:

0.625

AC XY:

454704

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.848

AC:

28385

AN:

33480

American (AMR)

AF:

0.527

AC:

23582

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.725

AC:

18949

AN:

26136

East Asian (EAS)

AF:

0.495

AC:

19665

AN:

39698

South Asian (SAS)

AF:

0.492

AC:

42459

AN:

86258

European-Finnish (FIN)

AF:

0.560

AC:

29910

AN:

53406

Middle Eastern (MID)

AF:

0.677

AC:

3905

AN:

5766

European-Non Finnish (NFE)

AF:

0.643

AC:

714626

AN:

1111870

Other (OTH)

AF:

0.644

AC:

38897

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

21915

43830

65745

87660

109575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18790

37580

56370

75160

93950

<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:

0.679

AC:

103276

AN:

152090

Hom.:

36046

Cov.:

AF XY:

0.671

AC XY:

49891

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.835

AC:

34653

AN:

41510

American (AMR)

AF:

0.607

AC:

9269

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.721

AC:

2501

AN:

3470

East Asian (EAS)

AF:

0.522

AC:

2696

AN:

5162

South Asian (SAS)

AF:

0.480

AC:

2310

AN:

4808

European-Finnish (FIN)

AF:

0.550

AC:

5820

AN:

10578

Middle Eastern (MID)

AF:

0.680

AC:

200

AN:

294

European-Non Finnish (NFE)

AF:

0.643

AC:

43693

AN:

67970

Other (OTH)

AF:

0.703

AC:

1487

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1600

3199

4799

6398

7998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

800

1600

2400

3200

4000

<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:

0.657

Hom.:

168674

Bravo

AF:

0.694

TwinsUK

AF:

0.645

AC:

2393

ALSPAC

AF:

0.655

AC:

2525

ESP6500AA

AF:

0.829

AC:

3652

ESP6500EA

AF:

0.652

AC:

5606

ExAC

AF:

0.619

AC:

75103

Asia WGS

AF:

0.498

AC:

1737

AN:

3478

EpiCase

AF:

0.651

EpiControl

AF:

0.659

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 28, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 07, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Osteogenesis imperfecta type 6

Benign:3

Medical Molecular Genetics Department, National Research Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Osteogenesis imperfecta

Benign:1

Jul 18, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

1.2

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.14

T;T;T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.084

T;T;T;T;T

MetaRNN

Benign

0.0000017

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.97

L;.;.;.;.

PhyloP100

-0.72

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.50

N;.;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.27

T;.;.;.;.

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

0.0050

B;.;.;.;.

Vest4

0.080

MPC

0.072

ClinPred

0.029

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.013

gMVP

0.30

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over