dbSNP rs1553774731: SERPINI1:p.Asn161Ser (chr3-167792590-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001122752.2(SERPINI1):c.482A>G(p.Asn161Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPINI1
NM_001122752.2 missense, splice_region

Scores

Splicing: ADA: 0.00009951

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a mutagenesis_site Increases protein stability and abolishes tendency to form polymers. No effect on inhibitory activity. (size 0) in uniprot entity NEUS_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.115744054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI1	NM_001122752.2 link	c.482A>G	p.Asn161Ser	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000446050.7	NP_001116224.1	Q99574A0A0S2Z455
SERPINI1	NM_005025.5 link	c.482A>G	p.Asn161Ser	missense_variant, splice_region_variant	Exon 4 of 9		NP_005016.1	Q99574A0A0S2Z455
SERPINI1	XM_017006618.3 link	c.482A>G	p.Asn161Ser	missense_variant, splice_region_variant	Exon 4 of 9		XP_016862107.1	Q99574A0A0S2Z455

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINI1	ENST00000446050.7 link	c.482A>G	p.Asn161Ser	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_001122752.2	ENSP00000397373.2	Q99574
SERPINI1	ENST00000295777.9 link	c.482A>G	p.Asn161Ser	missense_variant, splice_region_variant	Exon 4 of 9	1		ENSP00000295777.5	Q99574
SERPINI1	ENST00000472747.2 link	c.482A>G	p.Asn161Ser	missense_variant, splice_region_variant	Exon 4 of 5	3		ENSP00000420561.2	C9JDY5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460716

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.44

DEOGEN2

Benign

0.22

T;T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.74

.;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.27

N;N;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.63

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.086

MutPred

0.59

Loss of ubiquitination at K164 (P = 0.0811);Loss of ubiquitination at K164 (P = 0.0811);Loss of ubiquitination at K164 (P = 0.0811);

MVP

0.31

MPC

0.073

ClinPred

0.23

GERP RS

-1.2

Varity_R

0.24

gMVP

0.062

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.0060

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over