rs61735307

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001122752.2(SERPINI1):c.40A>G(p.Ser14Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 1,614,172 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. S14N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 5 hom. )

Consequence

SERPINI1
NM_001122752.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.76

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048808157).

BP6

Variant 3-167789168-A-G is Benign according to our data. Variant chr3-167789168-A-G is described in ClinVar as [Benign]. Clinvar id is 344119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-167789168-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 338 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SERPINI1	NM_001122752.2 linkuse as main transcript	c.40A>G	p.Ser14Gly	missense_variant	2/9	ENST00000446050.7
SERPINI1	NM_005025.5 linkuse as main transcript	c.40A>G	p.Ser14Gly	missense_variant	2/9
SERPINI1	XM_017006618.3 linkuse as main transcript	c.40A>G	p.Ser14Gly	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SERPINI1	ENST00000446050.7 linkuse as main transcript	c.40A>G	p.Ser14Gly	missense_variant	2/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9 linkuse as main transcript	c.40A>G	p.Ser14Gly	missense_variant	2/9	1		P1
SERPINI1	ENST00000472747.2 linkuse as main transcript	c.40A>G	p.Ser14Gly	missense_variant	2/5	3
SERPINI1	ENST00000472941.5 linkuse as main transcript	c.40A>G	p.Ser14Gly	missense_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.00222

AC:

338

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00798

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000684

AC:

172

AN:

251408

Hom.:

AF XY:

0.000500

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00947

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000235

AC:

343

AN:

1461806

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

137

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00839

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.00221

AC:

337

AN:

152366

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

162

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00794

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000431

Hom.:

Bravo

AF:

0.00246

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000857

AC:

104

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 23, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.019

T;T;T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.42

T;.;T;T

MetaRNN

Benign

0.0049

T;T;T;T

MetaSVM

Benign

-0.51

MutationTaster

Benign

0.90

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.62

N;N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.0070

D;T;T;T

Sift4G

Uncertain

0.031

D;T;T;T

Polyphen

0.15

.;B;B;.

Vest4

0.15, 0.15

MVP

0.51

MPC

0.083

ClinPred

0.021

GERP RS

4.1

Varity_R

0.063

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.47

Position offset: 1

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