rs767144751

Positions:

chr3-167790594-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001122752.2(SERPINI1):c.473A>G(p.Asn158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,611,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

SERPINI1
NM_001122752.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.52

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17794496).

BP6

Variant 3-167790594-A-G is Benign according to our data. Variant chr3-167790594-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 466617.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINI1	NM_001122752.2 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/9	ENST00000446050.7	NP_001116224.1	Q99574A0A0S2Z455
SERPINI1	NM_005025.5 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/9		NP_005016.1	Q99574A0A0S2Z455
SERPINI1	XM_017006618.3 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/9		XP_016862107.1	Q99574A0A0S2Z455

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SERPINI1	ENST00000446050.7 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/9	1	NM_001122752.2	ENSP00000397373.2	Q99574
SERPINI1	ENST00000295777.9 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/9	1		ENSP00000295777.5	Q99574
SERPINI1	ENST00000472747.2 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/5	3		ENSP00000420561.2	C9JDY5
SERPINI1	ENST00000472941.5 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/3	3		ENSP00000420133.1	C9JQU8

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000440

AC:

AN:

249888

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135070

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000601

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1458904

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725972

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2021

The c.473A>G (p.N158S) alteration is located in exon 3 (coding exon 2) of the SERPINI1 gene. This alteration results from a A to G substitution at nucleotide position 473, causing the asparagine (N) at amino acid position 158 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Familial encephalopathy with neuroserpin inclusion bodies

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

T;T;T;T

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.81

T;.;T;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.5

.;L;L;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.42

N;N;N;N

REVEL

Uncertain

0.31

Sift

Benign

0.072

T;T;T;T

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.071

MutPred

0.47

Gain of methylation at K153 (P = 0.1283);Gain of methylation at K153 (P = 0.1283);Gain of methylation at K153 (P = 0.1283);Gain of methylation at K153 (P = 0.1283);

MVP

0.61

MPC

0.073

ClinPred

0.18

GERP RS

3.0

Varity_R

0.16

gMVP

0.29

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