rs146948408

Positions:

• chr3-167789205-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000446050.7(SERPINI1):​c.77T>C​(p.Ile26Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,614,208 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. I26V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: SERPINI1 ENST00000446050.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.12

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=0.004885435).
• BP6: Variant 3-167789205-T-C is Benign according to our data. Variant chr3-167789205-T-C is described in ClinVar as [Benign]. Clinvar id is 235396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-167789205-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00108 (1586/1461828) while in subpopulation AMR AF= 0.0183 (817/44724). AF 95% confidence interval is 0.0172. There are 18 homozygotes in gnomad4_exome. There are 666 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 249 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.77T>C	p.Ile26Thr	missense_variant	2/9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.77T>C	p.Ile26Thr	missense_variant	2/9		NP_005016.1
SERPINI1	XM_017006618.3	c.77T>C	p.Ile26Thr	missense_variant	2/9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.77T>C	p.Ile26Thr	missense_variant	2/9	1	NM_001122752.2	ENSP00000397373	P1
SERPINI1	ENST00000295777.9	c.77T>C	p.Ile26Thr	missense_variant	2/9	1		ENSP00000295777	P1
SERPINI1	ENST00000472747.2	c.77T>C	p.Ile26Thr	missense_variant	2/5	3		ENSP00000420561
SERPINI1	ENST00000472941.5	c.77T>C	p.Ile26Thr	missense_variant	2/3	3		ENSP00000420133

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152262 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0171

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00422 AC: 1060 AN: 251428 Hom.: 13 AF XY: 0.00316 AC XY: 430 AN XY: 135882

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0176

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00108 AC: 1586 AN: 1461828 Hom.: 18 Cov.: 31 AF XY: 0.000916 AC XY: 666 AN XY: 727210

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0151

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00163 AC: 249 AN: 152380 Hom.: 2 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74508

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00843

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000584 Hom.: 1

Bravo AF: 0.00300

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00318 AC: 386

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 13, 2016	- -

Familial encephalopathy with neuroserpin inclusion bodies Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

SERPINI1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	13
DANN	Benign	0.14
DEOGEN2	Benign	0.082	T;T;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.76	T;.;T;T
MetaRNN	Benign	0.0049	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.59	.;N;N;.
MutationTaster	Benign	0.69	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.37	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.084	T;T;T;T
Polyphen		0.024	.;B;B;.
Vest4		0.14, 0.15
MVP		0.10
MPC		0.12
ClinPred		0.011	T
GERP RS		5.2
Varity_R		0.24
gMVP		0.42

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: rs146948408; hg19: chr3-167506993;