rs1553774731

Positions:

• chr3-167792590-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001122752.2(SERPINI1):​c.482A>T​(p.Asn161Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SERPINI1 NM_001122752.2 missense, splice_region
• Scores: Splicing: ADA: 0.001002
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI1	NM_001122752.2	c.482A>T	p.Asn161Ile	missense_variant, splice_region_variant	4/9	ENST00000446050.7
SERPINI1	NM_005025.5	c.482A>T	p.Asn161Ile	missense_variant, splice_region_variant	4/9
SERPINI1	XM_017006618.3	c.482A>T	p.Asn161Ile	missense_variant, splice_region_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000446050.7	c.482A>T	p.Asn161Ile	missense_variant, splice_region_variant	4/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9	c.482A>T	p.Asn161Ile	missense_variant, splice_region_variant	4/9	1		P1
SERPINI1	ENST00000472747.2	c.482A>T	p.Asn161Ile	missense_variant, splice_region_variant	4/5	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial encephalopathy with neuroserpin inclusion bodies Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with SERPINI1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with isoleucine at codon 161 of the SERPINI1 protein (p.Asn161Ile). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.65	D;D;D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	0.63	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		0.59	P;P;.
Vest4		0.35
MutPred		0.72		Loss of ubiquitination at K164 (P = 0.0547);Loss of ubiquitination at K164 (P = 0.0547);Loss of ubiquitination at K164 (P = 0.0547);
MVP		0.54
MPC		0.26
ClinPred		0.98	D
GERP RS		-1.2
Varity_R		0.85
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1553774731; hg19: chr3-167510378;