rs140116256

Positions:

• chr3-167790553-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001122752.2(SERPINI1):​c.432T>C​(p.Asn144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,888 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (6 hom.)
• Consequence: SERPINI1 NM_001122752.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.308

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-167790553-T-C is Benign according to our data. Variant chr3-167790553-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 344128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-167790553-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.308 with no splicing effect.
• BS2: High AC in GnomAd4 at 159 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.432T>C	p.Asn144=	synonymous_variant	3/9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.432T>C	p.Asn144=	synonymous_variant	3/9		NP_005016.1
SERPINI1	XM_017006618.3	c.432T>C	p.Asn144=	synonymous_variant	3/9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.432T>C	p.Asn144=	synonymous_variant	3/9	1	NM_001122752.2	ENSP00000397373	P1
SERPINI1	ENST00000295777.9	c.432T>C	p.Asn144=	synonymous_variant	3/9	1		ENSP00000295777	P1
SERPINI1	ENST00000472747.2	c.432T>C	p.Asn144=	synonymous_variant	3/5	3		ENSP00000420561
SERPINI1	ENST00000472941.5	c.432T>C	p.Asn144=	synonymous_variant	3/3	3		ENSP00000420133

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152232 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00175

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000928 AC: 233 AN: 251074 Hom.: 0 AF XY: 0.00105 AC XY: 142 AN XY: 135680

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00144 AC: 2106 AN: 1461656 Hom.: 6 Cov.: 31 AF XY: 0.00140 AC XY: 1016 AN XY: 727122

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00253

Gnomad4 NFE exome AF: 0.00165

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.000941 AC XY: 70 AN XY: 74378

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00175

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.000801

EpiCase AF: 0.000927

EpiControl AF: 0.00113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	SERPINI1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Familial encephalopathy with neuroserpin inclusion bodies Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.4
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140116256; hg19: chr3-167508341;