rs55872908

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001122752.2(SERPINI1):c.838G>A(p.Ala280Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,613,532 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. A280E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 16 hom., cov: 32)

Exomes 𝑓: 0.017 ( 256 hom. )

Consequence

SERPINI1
NM_001122752.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.66

Publications

9 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:

ENSG00000287319 (HGNC:):

ENSG00000287319 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=0.008110166).

BP6

Variant 3-167794781-G-A is Benign according to our data. Variant chr3-167794781-G-A is described in ClinVar as Benign. ClinVar VariationId is 344131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1652/152180) while in subpopulation NFE AF = 0.0172 (1168/68016). AF 95% confidence interval is 0.0164. There are 16 homozygotes in GnomAd4. There are 754 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1652 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SERPINI1	NM_001122752.2 link	c.838G>A	p.Ala280Thr	missense_variant	Exon 5 of 9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5 link	c.838G>A	p.Ala280Thr	missense_variant	Exon 5 of 9		NP_005016.1
SERPINI1	XM_017006618.3 link	c.838G>A	p.Ala280Thr	missense_variant	Exon 5 of 9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SERPINI1	ENST00000446050.7 link	c.838G>A	p.Ala280Thr	missense_variant	Exon 5 of 9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9 link	c.838G>A	p.Ala280Thr	missense_variant	Exon 5 of 9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2 link	c.*102G>A		downstream_gene_variant		3		ENSP00000420561.2
ENSG00000287319	ENST00000661269.1 link	n.*166C>T		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1652

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00341

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00859

Gnomad ASJ

AF:

0.0303

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00956

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.0114

AC:

2856

AN:

251164

AF XY:

0.0117

show subpopulations

Gnomad AFR exome

AF:

0.00351

Gnomad AMR exome

AF:

0.00561

Gnomad ASJ exome

AF:

0.0276

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0168

AC:

24532

AN:

1461352

Hom.:

256

Cov.:

AF XY:

0.0165

AC XY:

11984

AN XY:

726960

show subpopulations

African (AFR)

AF:

0.00287

AC:

AN:

33450

American (AMR)

AF:

0.00644

AC:

287

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.0292

AC:

762

AN:

26120

East Asian (EAS)

AF:

0.000101

AC:

AN:

39696

South Asian (SAS)

AF:

0.0105

AC:

905

AN:

86246

European-Finnish (FIN)

AF:

0.00412

AC:

220

AN:

53416

Middle Eastern (MID)

AF:

0.00982

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.0190

AC:

21117

AN:

1111754

Other (OTH)

AF:

0.0180

AC:

1085

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1244

2488

3731

4975

6219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.0109

AC:

1652

AN:

152180

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

754

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.00340

AC:

141

AN:

41518

American (AMR)

AF:

0.00858

AC:

131

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0303

AC:

105

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.00977

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00301

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1168

AN:

68016

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

168

251

335

419

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0150

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0195

AC:

168

ExAC

AF:

0.0112

AC:

1354

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0174

EpiControl

AF:

0.0165

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 05, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial encephalopathy with neuroserpin inclusion bodies

Benign:2

Jan 12, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SERPINI1-related disorder

Benign:1

Jun 05, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.041

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.0081

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.14

N;N

PhyloP100

7.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.56

N;N

REVEL

Uncertain

0.50

Sift

Benign

0.55

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.094

B;B

Vest4

0.12

MPC

0.13

ClinPred

0.019

GERP RS

5.7

Varity_R

0.62

gMVP

0.37

Mutation Taster

=90/10

polymorphism

(source)

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

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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