3-167735915-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000295777.9(SERPINI1):c.-239G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,152 control chromosomes in the GnomAD database, including 2,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2407 hom., cov: 32)
  • Exomes 𝑓: 0.056 (0 hom.)
• Consequence: SERPINI1 ENST00000295777.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.578

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-167735915-G-A is Benign according to our data. Variant chr3-167735915-G-A is described in ClinVar as [Benign]. Clinvar id is 344116.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI1	NM_001122752.2	c.-19+92G>A		intron_variant		ENST00000446050.7
SERPINI1	NM_005025.5	c.-239G>A		5_prime_UTR_variant	1/9
SERPINI1	XM_017006618.3	c.-19+103G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000295777.9	c.-239G>A		5_prime_UTR_variant	1/9	1		P1
SERPINI1	ENST00000446050.7	c.-19+92G>A		intron_variant		1	NM_001122752.2	P1
SERPINI1	ENST00000472747.2	c.-19+103G>A		intron_variant		3
SERPINI1	ENST00000472941.5	c.-19+590G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25210 AN: 152016 Hom.: 2407 Cov.: 32

Gnomad AFR AF: 0.0927

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0255

Gnomad SAS AF: 0.0833

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.152

GnomAD4 exome AF: 0.0556 AC: 1 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.0833 AC XY: 1 AN XY: 12

Gnomad4 NFE exome AF: 0.0625

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.166 AC: 25214 AN: 152134 Hom.: 2407 Cov.: 32 AF XY: 0.161 AC XY: 11963 AN XY: 74352

Gnomad4 AFR AF: 0.0926

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.0256

Gnomad4 SAS AF: 0.0836

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.151

Alfa AF: 0.145 Hom.: 483

Bravo AF: 0.154

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral cavernous malformation 3 Benign:1

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. -

Familial encephalopathy with neuroserpin inclusion bodies Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	3.2
Dann	Benign	0.82

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: rs9835352; hg19: chr3-167453703;