3-167789171-A-G

Position:

• chr3-167789171-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001122752.2(SERPINI1):​c.43A>G​(p.Met15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.228

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0534392).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.43A>G	p.Met15Val	missense_variant	2/9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.43A>G	p.Met15Val	missense_variant	2/9		NP_005016.1
SERPINI1	XM_017006618.3	c.43A>G	p.Met15Val	missense_variant	2/9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.43A>G	p.Met15Val	missense_variant	2/9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9	c.43A>G	p.Met15Val	missense_variant	2/9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2	c.43A>G	p.Met15Val	missense_variant	2/5	3		ENSP00000420561.2
SERPINI1	ENST00000472941.5	c.43A>G	p.Met15Val	missense_variant	2/3	3		ENSP00000420133.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461806 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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 19, 2022

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. ClinVar contains an entry for this variant (Variation ID: 1513397). This variant has not been reported in the literature in individuals affected with SERPINI1-related conditions. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 15 of the SERPINI1 protein (p.Met15Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.014
DANN	Benign	0.31
DEOGEN2	Benign	0.0033	T;T;T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.47	T;.;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.053	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.20	.;N;N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.080	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.56	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.032, 0.030
MutPred		0.40		Loss of phosphorylation at T20 (P = 0.0851);Loss of phosphorylation at T20 (P = 0.0851);Loss of phosphorylation at T20 (P = 0.0851);Loss of phosphorylation at T20 (P = 0.0851);
MVP		0.39
MPC		0.092
ClinPred		0.012	T
GERP RS		-9.3
Varity_R		0.033
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1727411590; hg19: chr3-167506959;