3-167794703-A-C

Position:

• chr3-167794703-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001122752.2(SERPINI1):​c.760A>C​(p.Met254Leu) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M254T) 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: 7.09

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36311784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI1	NM_001122752.2	c.760A>C	p.Met254Leu	missense_variant	5/9	ENST00000446050.7
SERPINI1	NM_005025.5	c.760A>C	p.Met254Leu	missense_variant	5/9
SERPINI1	XM_017006618.3	c.760A>C	p.Met254Leu	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000446050.7	c.760A>C	p.Met254Leu	missense_variant	5/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9	c.760A>C	p.Met254Leu	missense_variant	5/9	1		P1
SERPINI1	ENST00000472747.2			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 06, 2017

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 missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 methionine with leucine at codon 254 of the SERPINI1 protein (p.Met254Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.067
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.23	N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.64	N;N
REVEL	Uncertain	0.41
Sift	Benign	0.98	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.0	B;B
Vest4		0.60
MutPred		0.53		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.64
MPC		0.085
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553774956; hg19: chr3-167512491;