rs1553774967

Variant names:

• chr3-167794786-C-G
• rs1553774967
• NM_001122752.2:c.843C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-167794786-C-G
• chr3-167794786-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122752.2(SERPINI1):​c.843C>G​(p.Asn281Lys) variant causes a missense 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N281H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.608
• 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)

ENSG00000287319 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20131627).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.843C>G	p.Asn281Lys	missense_variant	Exon 5 of 9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.843C>G	p.Asn281Lys	missense_variant	Exon 5 of 9		NP_005016.1
SERPINI1	XM_017006618.3	c.843C>G	p.Asn281Lys	missense_variant	Exon 5 of 9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.843C>G	p.Asn281Lys	missense_variant	Exon 5 of 9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9	c.843C>G	p.Asn281Lys	missense_variant	Exon 5 of 9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2	c.*107C>G		downstream_gene_variant		3		ENSP00000420561.2
ENSG00000287319	ENST00000661269.1	n.*161G>C		downstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

May 14, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine with lysine at codon 281 of the SERPINI1 protein (p.Asn281Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SERPINI1-related disease. 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 C65"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.2	L;L
PhyloP100		0.61
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.090
Sift	Benign	0.13	T;T
Sift4G	Benign	0.45	T;T
Polyphen		0.15	B;B
Vest4		0.42
MutPred		0.36		Gain of methylation at N281 (P = 0.0158);Gain of methylation at N281 (P = 0.0158);
MVP		0.25
MPC		0.12
ClinPred		0.25	T
GERP RS		3.9
Varity_R		0.46
gMVP		0.33
Mutation Taster		=35/65	disease causing

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: rs1553774967; hg19: chr3-167512574;