NM_001122752.2:c.518A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

progressive myoclonus epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
familial encephalopathy with neuroserpin inclusion bodies
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

SERPINI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 344129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 444 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122752.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINI1	NM_001122752.2	MANE Select	c.518A>G	p.Asp173Gly	missense	Exon 4 of 9	NP_001116224.1	A0A0S2Z455
	SERPINI1	NM_005025.5		c.518A>G	p.Asp173Gly	missense	Exon 4 of 9	NP_005016.1	A0A0S2Z455

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINI1	ENST00000446050.7	TSL:1 MANE Select	c.518A>G	p.Asp173Gly	missense	Exon 4 of 9	ENSP00000397373.2	Q99574
SERPINI1	ENST00000295777.9	TSL:1	c.518A>G	p.Asp173Gly	missense	Exon 4 of 9	ENSP00000295777.5	Q99574
SERPINI1	ENST00000872947.1		c.518A>G	p.Asp173Gly	missense	Exon 4 of 9	ENSP00000543006.1

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

GnomAD2 exomes

AF:

0.00102

AC:

256

AN:

250994

AF XY:

0.000877

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 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

African (AFR)

AF:

0.00935

AC:

313

AN:

33462

American (AMR)

AF:

0.00211

AC:

AN:

44622

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000154

AC:

171

AN:

1111854

Other (OTH)

AF:

0.00141

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00292

AC:

444

AN:

152210

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

227

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00809

AC:

336

AN:

41530

American (AMR)

AF:

0.00537

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68020

Other (OTH)

AF:

0.00332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00110

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial encephalopathy with neuroserpin inclusion bodies (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.30

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0070

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.61

PhyloP100

2.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.1

REVEL

Benign

0.25

Sift

Benign

0.70

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.10

MVP

0.23

MPC

0.12

ClinPred

0.022

GERP RS

2.9

Varity_R

0.28

gMVP

0.50

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over