3-167735819-G-A

Variant names:

• chr3-167735819-G-A
• rs886058166
• NM_001122752.2:c.-23G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001122752.2(SERPINI1):​c.-23G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 152,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPINI1 NM_001122752.2 5_prime_UTR
• Scores: Splicing: ADA: 0.0003362
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58
• Publications: 0 publications found

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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BS2: High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.-23G>A		5_prime_UTR_variant	Exon 1 of 9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.-335G>A		5_prime_UTR_variant	Exon 1 of 9		NP_005016.1
SERPINI1	XM_017006618.3	c.-19+7G>A		splice_region_variant, intron_variant	Intron 1 of 8		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.-23G>A		5_prime_UTR_variant	Exon 1 of 9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9	c.-335G>A		5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2	c.-19+7G>A		splice_region_variant, intron_variant	Intron 1 of 4	3		ENSP00000420561.2
SERPINI1	ENST00000472941.5	c.-19+494G>A		intron_variant	Intron 1 of 2	3		ENSP00000420133.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 150 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 118

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 132

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74478

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000200

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial encephalopathy with neuroserpin inclusion bodies Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.97
PhyloP100		2.6
PromoterAI		0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=298/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886058166; hg19: chr3-167453607;