rs61735306

chr3-167789234-C-Achr3-167789234-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001122752.2(SERPINI1):c.106C>A(p.Arg36Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,614,004 control chromosomes in the GnomAD database, including 1 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.31

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033968598).
• BP6: Variant 3-167789234-C-A is Benign according to our data. Variant chr3-167789234-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 344121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-167789234-C-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI1	NM_001122752.2	c.106C>A	p.Arg36Ser	missense_variant	2/9	ENST00000446050.7
SERPINI1	NM_005025.5	c.106C>A	p.Arg36Ser	missense_variant	2/9
SERPINI1	XM_017006618.3	c.106C>A	p.Arg36Ser	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000446050.7	c.106C>A	p.Arg36Ser	missense_variant	2/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9	c.106C>A	p.Arg36Ser	missense_variant	2/9	1		P1
SERPINI1	ENST00000472747.2	c.106C>A	p.Arg36Ser	missense_variant	2/5	3
SERPINI1	ENST00000472941.5	c.106C>A	p.Arg36Ser	missense_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000867 AC: 132 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000998 AC: 251 AN: 251416 Hom.: 3 AF XY: 0.00102 AC XY: 139 AN XY: 135880

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00177

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00129 AC: 1880 AN: 1461834 Hom.: 1 Cov.: 31 AF XY: 0.00130 AC XY: 947 AN XY: 727212

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000406

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.00154

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.000867 AC: 132 AN: 152170 Hom.: 0 Cov.: 33 AF XY: 0.000699 AC XY: 52 AN XY: 74340

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00165

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.000861

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00112 AC: 136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely 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	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

SERPINI1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2020

This variant is classified as likely 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	0.24
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.097	T;T;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.00041
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;.;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	0.91	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.81	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.032	.;B;B;.
Vest4		0.23, 0.23
MVP		0.47
MPC		0.11
ClinPred		0.0040	T
GERP RS		5.2
Varity_R		0.25
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61735306; hg19: chr3-167507022;