3-167789149-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001122752.2(SERPINI1):c.21C>G(p.Phe7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0971 in 1,613,114 control chromosomes in the GnomAD database, including 8,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F7S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1465 hom., cov: 33)
  • Exomes 𝑓: 0.094 (7184 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.48

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002107948).
• BP6: Variant 3-167789149-C-G is Benign according to our data. Variant chr3-167789149-C-G is described in ClinVar as [Benign]. Clinvar id is 344118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-167789149-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI1	NM_001122752.2	c.21C>G	p.Phe7Leu	missense_variant	2/9	ENST00000446050.7
SERPINI1	NM_005025.5	c.21C>G	p.Phe7Leu	missense_variant	2/9
SERPINI1	XM_017006618.3	c.21C>G	p.Phe7Leu	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000446050.7	c.21C>G	p.Phe7Leu	missense_variant	2/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9	c.21C>G	p.Phe7Leu	missense_variant	2/9	1		P1
SERPINI1	ENST00000472747.2	c.21C>G	p.Phe7Leu	missense_variant	2/5	3
SERPINI1	ENST00000472941.5	c.21C>G	p.Phe7Leu	missense_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19195 AN: 152094 Hom.: 1457 Cov.: 33

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.0678

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0905

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.0996 AC: 25033 AN: 251304 Hom.: 1575 AF XY: 0.0916 AC XY: 12444 AN XY: 135846

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.0584

Gnomad EAS exome AF: 0.0568

Gnomad SAS exome AF: 0.0379

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.0876

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.0941 AC: 137465 AN: 1460902 Hom.: 7184 Cov.: 32 AF XY: 0.0915 AC XY: 66516 AN XY: 726832

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.0591

Gnomad4 EAS exome AF: 0.0707

Gnomad4 SAS exome AF: 0.0375

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.0924

Gnomad4 OTH exome AF: 0.0950

GnomAD4 genome AF: 0.126 AC: 19243 AN: 152212 Hom.: 1465 Cov.: 33 AF XY: 0.127 AC XY: 9431 AN XY: 74434

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.0568

Gnomad4 EAS AF: 0.0675

Gnomad4 SAS AF: 0.0358

Gnomad4 FIN AF: 0.151

Gnomad4 NFE AF: 0.0905

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0935 Hom.: 232

Bravo AF: 0.131

TwinsUK AF: 0.0906 AC: 336

ALSPAC AF: 0.0908 AC: 350

ESP6500AA AF: 0.199 AC: 875

ESP6500EA AF: 0.0881 AC: 758

ExAC AF: 0.0979 AC: 11891

Asia WGS AF: 0.0810 AC: 281 AN: 3478

EpiCase AF: 0.0887

EpiControl AF: 0.0856

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Familial encephalopathy with neuroserpin inclusion bodies Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	14
Dann	Benign	0.54
DEOGEN2	Benign	0.0079	T;T;T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.46	T;.;T;T
MetaRNN	Benign	0.0021	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.17	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.65	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.026, 0.025
MutPred		0.57		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MPC		0.11
ClinPred		0.0015	T
GERP RS		1.8
Varity_R		0.048
gMVP		0.17

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: rs33917740; hg19: chr3-167506937; COSMIC: COSV55509515;