3-167735845-G-T

Variant names:

• chr3-167735845-G-T
• rs1559989168
• ENST00000295777.9:c.-309G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001122752.2(SERPINI1):​c.-19+22G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPINI1 NM_001122752.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.175
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.-19+22G>T		intron_variant	Intron 1 of 8	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.-309G>T		5_prime_UTR_variant	Exon 1 of 9		NP_005016.1
SERPINI1	XM_017006618.3	c.-19+33G>T		intron_variant	Intron 1 of 8		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000295777.9	c.-309G>T		5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000295777.5
SERPINI1	ENST00000446050.7	c.-19+22G>T		intron_variant	Intron 1 of 8	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000472747.2	c.-19+33G>T		intron_variant	Intron 1 of 4	3		ENSP00000420561.2
SERPINI1	ENST00000472941.5	c.-19+520G>T		intron_variant	Intron 1 of 2	3		ENSP00000420133.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 126 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 92

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

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

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: 110

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial encephalopathy with neuroserpin inclusion bodies Uncertain:1

Mar 02, 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	-0.82
CADD	Benign	6.6
DANN	Benign	0.63
PhyloP100		-0.17
PromoterAI		-0.033	Neutral

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

Other links and lift over

dbSNP: rs1559989168; hg19: chr3-167453633;