chr3-167789169-G-A

Position:

• chr3-167789169-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122752.2(SERPINI1):​c.41G>A​(p.Ser14Asn) 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. 14/21 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. S14G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2047543).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI1	NM_001122752.2	c.41G>A	p.Ser14Asn	missense_variant	2/9	ENST00000446050.7
SERPINI1	NM_005025.5	c.41G>A	p.Ser14Asn	missense_variant	2/9
SERPINI1	XM_017006618.3	c.41G>A	p.Ser14Asn	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000446050.7	c.41G>A	p.Ser14Asn	missense_variant	2/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9	c.41G>A	p.Ser14Asn	missense_variant	2/9	1		P1
SERPINI1	ENST00000472747.2	c.41G>A	p.Ser14Asn	missense_variant	2/5	3
SERPINI1	ENST00000472941.5	c.41G>A	p.Ser14Asn	missense_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 14 of the SERPINI1 protein (p.Ser14Asn). This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SERPINI1 protein function. This variant has not been reported in the literature in individuals affected with SERPINI1-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T;T;T;T
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.42	T;.;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.2	.;M;M;.
MutationTaster	Benign	0.94	N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.49	N;N;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.028	D;T;T;T
Polyphen		0.45	.;P;P;.
Vest4		0.38, 0.37
MutPred		0.41		Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);Loss of helix (P = 0.0017);
MVP		0.64
MPC		0.11
ClinPred		0.47	T
GERP RS		5.2
Varity_R		0.11
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-167506957;