NM_001122752.2:c.21C>G

Variant names:

Variant summary

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

The NM_001122752.2(SERPINI1):c.21C>G(p.Phe7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0971 in 1,613,114 control chromosomes in the GnomAD database, including 8,649 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F7S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.13 ( 1465 hom., cov: 33)

Exomes 𝑓: 0.094 ( 7184 hom. )

Consequence

SERPINI1
NM_001122752.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.48

Publications

10 publications found

Variant links:

Genes affected

SERPINI1 (HGNC:8943): (serpin family I member 1) This gene encodes a member of the serpin superfamily of serine proteinase inhibitors. The protein is primarily secreted by axons in the brain, and preferentially reacts with and inhibits tissue-type plasminogen activator. It is thought to play a role in the regulation of axonal growth and the development of synaptic plasticity. Mutations in this gene result in familial encephalopathy with neuroserpin inclusion bodies (FENIB), which is a dominantly inherited form of familial encephalopathy and epilepsy characterized by the accumulation of mutant neuroserpin polymers. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

SERPINI1 Gene-Disease associations (from GenCC):

progressive myoclonus epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
familial encephalopathy with neuroserpin inclusion bodies
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

SERPINI1 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=0.002107948).

BP6

Variant 3-167789149-C-G is Benign according to our data. Variant chr3-167789149-C-G is described in ClinVar as [Benign]. Clinvar id is 344118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI1	NM_001122752.2 link	c.21C>G	p.Phe7Leu	missense_variant	Exon 2 of 9	ENST00000446050.7	NP_001116224.1	Q99574A0A0S2Z455
SERPINI1	NM_005025.5 link	c.21C>G	p.Phe7Leu	missense_variant	Exon 2 of 9		NP_005016.1	Q99574A0A0S2Z455
SERPINI1	XM_017006618.3 link	c.21C>G	p.Phe7Leu	missense_variant	Exon 2 of 9		XP_016862107.1	Q99574A0A0S2Z455

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINI1	ENST00000446050.7 link	c.21C>G	p.Phe7Leu	missense_variant	Exon 2 of 9	1	NM_001122752.2	ENSP00000397373.2	Q99574
SERPINI1	ENST00000295777.9 link	c.21C>G	p.Phe7Leu	missense_variant	Exon 2 of 9	1		ENSP00000295777.5	Q99574
SERPINI1	ENST00000472747.2 link	c.21C>G	p.Phe7Leu	missense_variant	Exon 2 of 5	3		ENSP00000420561.2	C9JDY5
SERPINI1	ENST00000472941.5 link	c.21C>G	p.Phe7Leu	missense_variant	Exon 2 of 3	3		ENSP00000420133.1	C9JQU8

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19195

AN:

152094

Hom.:

1457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.118

Gnomad ASJ

AF:

0.0568

Gnomad EAS

AF:

0.0678

Gnomad SAS

AF:

0.0362

Gnomad FIN

AF:

0.151

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0905

Gnomad OTH

AF:

0.107

GnomAD2 exomes

AF:

0.0996

AC:

25033

AN:

251304

AF XY:

0.0916

show subpopulations

Gnomad AFR exome

AF:

0.212

Gnomad AMR exome

AF:

0.152

Gnomad ASJ exome

AF:

0.0584

Gnomad EAS exome

AF:

0.0568

Gnomad FIN exome

AF:

0.137

Gnomad NFE exome

AF:

0.0876

Gnomad OTH exome

AF:

0.104

GnomAD4 exome

AF:

0.0941

AC:

137465

AN:

1460902

Hom.:

7184

Cov.:

AF XY:

0.0915

AC XY:

66516

AN XY:

726832

show subpopulations

African (AFR)

AF:

0.210

AC:

7030

AN:

33442

American (AMR)

AF:

0.151

AC:

6735

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0591

AC:

1545

AN:

26126

East Asian (EAS)

AF:

0.0707

AC:

2808

AN:

39690

South Asian (SAS)

AF:

0.0375

AC:

3232

AN:

86244

European-Finnish (FIN)

AF:

0.134

AC:

7165

AN:

53286

Middle Eastern (MID)

AF:

0.0875

AC:

504

AN:

5760

European-Non Finnish (NFE)

AF:

0.0924

AC:

102712

AN:

1111280

Other (OTH)

AF:

0.0950

AC:

5734

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

6702

13404

20105

26807

33509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.126

AC:

19243

AN:

152212

Hom.:

1465

Cov.:

AF XY:

0.127

AC XY:

9431

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.208

AC:

8627

AN:

41512

American (AMR)

AF:

0.118

AC:

1803

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0568

AC:

197

AN:

3470

East Asian (EAS)

AF:

0.0675

AC:

350

AN:

5182

South Asian (SAS)

AF:

0.0358

AC:

173

AN:

4830

European-Finnish (FIN)

AF:

0.151

AC:

1605

AN:

10606

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0905

AC:

6157

AN:

68008

Other (OTH)

AF:

0.109

AC:

231

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

820

1640

2461

3281

4101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0935

Hom.:

232

Bravo

AF:

0.131

TwinsUK

AF:

0.0906

AC:

336

ALSPAC

AF:

0.0908

AC:

350

ESP6500AA

AF:

0.199

AC:

875

ESP6500EA

AF:

0.0881

AC:

758

ExAC

AF:

0.0979

AC:

11891

Asia WGS

AF:

0.0810

AC:

281

AN:

3478

EpiCase

AF:

0.0887

EpiControl

AF:

0.0856

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

May 05, 2021

GeneDx

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

- -

Familial encephalopathy with neuroserpin inclusion bodies

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.0079

T;T;T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.46

T;.;T;T

MetaRNN

Benign

0.0021

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.3

.;N;N;.

PhyloP100

1.5

PrimateAI

Benign

0.40

PROVEAN

Benign

0.17

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.65

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.026, 0.025

MutPred

0.57

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MPC

0.11

ClinPred

0.0015

GERP RS

1.8

Varity_R

0.048

gMVP

0.17

Mutation Taster

=99/1

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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NM_001122752.2:c.21C>G

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