rs61735309

Positions:

chr3-167792626-A-G

Variant summary

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

The NM_001122752.2(SERPINI1):c.518A>G(p.Asp173Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,613,672 control chromosomes in the GnomAD database, including 7 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 3 hom., cov: 31)

Exomes 𝑓: 0.00047 ( 4 hom. )

Consequence

SERPINI1
NM_001122752.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.46

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=0.007047981).

BP6

Variant 3-167792626-A-G is Benign according to our data. Variant chr3-167792626-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 344129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 444 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SERPINI1	NM_001122752.2 linkuse as main transcript	c.518A>G	p.Asp173Gly	missense_variant	4/9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5 linkuse as main transcript	c.518A>G	p.Asp173Gly	missense_variant	4/9		NP_005016.1
SERPINI1	XM_017006618.3 linkuse as main transcript	c.518A>G	p.Asp173Gly	missense_variant	4/9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SERPINI1	ENST00000446050.7 linkuse as main transcript	c.518A>G	p.Asp173Gly	missense_variant	4/9	1	NM_001122752.2	ENSP00000397373	P1
SERPINI1	ENST00000295777.9 linkuse as main transcript	c.518A>G	p.Asp173Gly	missense_variant	4/9	1		ENSP00000295777	P1
SERPINI1	ENST00000472747.2 linkuse as main transcript	c.518A>G	p.Asp173Gly	missense_variant	4/5	3		ENSP00000420561

Frequencies

GnomAD3 genomes

AF:

0.00290

AC:

441

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00804

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00538

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00102

AC:

256

AN:

250994

Hom.:

AF XY:

0.000877

AC XY:

119

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.00868

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000465

AC:

680

AN:

1461462

Hom.:

Cov.:

AF XY:

0.000453

AC XY:

329

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00935

Gnomad4 AMR exome

AF:

0.00211

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00292

AC:

444

AN:

152210

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

227

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00809

Gnomad4 AMR

AF:

0.00537

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00332

Alfa

AF:

0.000579

Hom.:

Bravo

AF:

0.00358

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000955

AC:

116

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000546

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 22, 2017	- -
Likely 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	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.14

DEOGEN2

Benign

0.30

T;T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.80

.;T;T

MetaRNN

Benign

0.0070

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.61

N;N;.

MutationTaster

Benign

0.52

D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.25

Sift

Benign

0.70

T;T;T

Sift4G

Benign

0.53

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.10

MVP

0.23

MPC

0.12

ClinPred

0.022

GERP RS

2.9

Varity_R

0.28

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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