rs139808176

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001122752.2(SERPINI1):c.218G>A(p.Arg73His) variant causes a missense change. The variant allele was found at a frequency of 0.00039 in 1,614,104 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. R73G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 4 hom. )

Consequence

SERPINI1
NM_001122752.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 5.94

Publications

5 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01201275).

BP6

Variant 3-167789346-G-A is Benign according to our data. Variant chr3-167789346-G-A is described in ClinVar as Benign. ClinVar VariationId is 344123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SERPINI1	NM_001122752.2 link	c.218G>A	p.Arg73His	missense_variant	Exon 2 of 9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5 link	c.218G>A	p.Arg73His	missense_variant	Exon 2 of 9		NP_005016.1
SERPINI1	XM_017006618.3 link	c.218G>A	p.Arg73His	missense_variant	Exon 2 of 9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SERPINI1	ENST00000446050.7 link	c.218G>A	p.Arg73His	missense_variant	Exon 2 of 9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9 link	c.218G>A	p.Arg73His	missense_variant	Exon 2 of 9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2 link	c.218G>A	p.Arg73His	missense_variant	Exon 2 of 5	3		ENSP00000420561.2
SERPINI1	ENST00000472941.5 link	c.218G>A	p.Arg73His	missense_variant	Exon 2 of 3	3		ENSP00000420133.1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000629

AC:

158

AN:

251224

AF XY:

0.000891

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000404

AC:

590

AN:

1461798

Hom.:

Cov.:

AF XY:

0.000556

AC XY:

404

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33478

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00502

AC:

433

AN:

86254

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000108

AC:

120

AN:

1111964

Other (OTH)

AF:

0.000464

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000263

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00580

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000582

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000741

AC:

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial encephalopathy with neuroserpin inclusion bodies

Benign:2

Dec 22, 2024

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.

SERPINI1-related disorder

Benign:1

Feb 24, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

T;T;T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;.;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

0.0

.;M;M;.

PhyloP100

5.9

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Uncertain

0.57

Sift

Benign

0.060

T;T;T;D

Sift4G

Benign

0.11

T;T;T;T

Vest4

0.0

ClinPred

0.068

GERP RS

3.4

Varity_R

0.41

gMVP

0.61

Mutation Taster

=91/9

polymorphism

(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