chr3-167789149-C-G

Position:

chr3-167789149-C-G

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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. 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

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=0.002107948).

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. Variant chr3-167789149-C-G is described in Lovd as [Benign].

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/exons	MANE
SERPINI1	NM_001122752.2 linkuse as main transcript	c.21C>G	p.Phe7Leu	missense_variant	2/9	ENST00000446050.7
SERPINI1	NM_005025.5 linkuse as main transcript	c.21C>G	p.Phe7Leu	missense_variant	2/9
SERPINI1	XM_017006618.3 linkuse as main transcript	c.21C>G	p.Phe7Leu	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SERPINI1	ENST00000446050.7 linkuse as main transcript	c.21C>G	p.Phe7Leu	missense_variant	2/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9 linkuse as main transcript	c.21C>G	p.Phe7Leu	missense_variant	2/9	1		P1
SERPINI1	ENST00000472747.2 linkuse as main transcript	c.21C>G	p.Phe7Leu	missense_variant	2/5	3
SERPINI1	ENST00000472941.5 linkuse as main transcript	c.21C>G	p.Phe7Leu	missense_variant	2/3	3

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

GnomAD3 exomes

AF:

0.0996

AC:

25033

AN:

251304

Hom.:

1575

AF XY:

0.0916

AC XY:

12444

AN XY:

135846

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 SAS exome

AF:

0.0379

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

Gnomad4 AFR exome

AF:

0.210

Gnomad4 AMR exome

AF:

0.151

Gnomad4 ASJ exome

AF:

0.0591

Gnomad4 EAS exome

AF:

0.0707

Gnomad4 SAS exome

AF:

0.0375

Gnomad4 FIN exome

AF:

0.134

Gnomad4 NFE exome

AF:

0.0924

Gnomad4 OTH exome

AF:

0.0950

GnomAD4 genome

AF:

0.126

AC:

19243

AN:

152212

Hom.:

1465

Cov.:

AF XY:

0.127

AC XY:

9431

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.208

Gnomad4 AMR

AF:

0.118

Gnomad4 ASJ

AF:

0.0568

Gnomad4 EAS

AF:

0.0675

Gnomad4 SAS

AF:

0.0358

Gnomad4 FIN

AF:

0.151

Gnomad4 NFE

AF:

0.0905

Gnomad4 OTH

AF:

0.109

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

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	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

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;.

MutationTaster

Benign

1.0

P;P

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

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

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