rs55872908

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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. A280S) 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:5

Conservation

PhyloP100: 7.66

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 344131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-167794781-G-A is described in Lovd as [Benign]. Variant chr3-167794781-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1652 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SERPINI1	NM_001122752.2 linkuse as main transcript	c.838G>A	p.Ala280Thr	missense_variant	5/9	ENST00000446050.7
SERPINI1	NM_005025.5 linkuse as main transcript	c.838G>A	p.Ala280Thr	missense_variant	5/9
SERPINI1	XM_017006618.3 linkuse as main transcript	c.838G>A	p.Ala280Thr	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000446050.7 linkuse as main transcript	c.838G>A	p.Ala280Thr	missense_variant	5/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9 linkuse as main transcript	c.838G>A	p.Ala280Thr	missense_variant	5/9	1		P1

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

GnomAD3 exomes

AF:

0.0114

AC:

2856

AN:

251164

Hom.:

AF XY:

0.0117

AC XY:

1590

AN XY:

135746

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 SAS exome

AF:

0.0102

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

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.00644

Gnomad4 ASJ exome

AF:

0.0292

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0105

Gnomad4 FIN exome

AF:

0.00412

Gnomad4 NFE exome

AF:

0.0190

Gnomad4 OTH exome

AF:

0.0180

GnomAD4 genome

AF:

0.0109

AC:

1652

AN:

152180

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

754

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00340

Gnomad4 AMR

AF:

0.00858

Gnomad4 ASJ

AF:

0.0303

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00977

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.0172

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.0153

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial encephalopathy with neuroserpin inclusion bodies

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 17, 2018

- -

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

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

MutationTaster

Benign

1.0

D;D;D

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

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