chr3-167735915-G-A

Variant names:

• chr3-167735915-G-A
• rs9835352
• ENST00000295777.9:c.-239G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001122752.2(SERPINI1):​c.-19+92G>A variant causes a intron 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 NM_001122752.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.578
• Publications: 5 publications found

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]

SERPINI1 Gene-Disease associations (from GenCC):

• progressive myoclonus epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• familial encephalopathy with neuroserpin inclusion bodies

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.-19+92G>A		intron_variant	Intron 1 of 8	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.-239G>A		5_prime_UTR_variant	Exon 1 of 9		NP_005016.1
SERPINI1	XM_017006618.3	c.-19+103G>A		intron_variant	Intron 1 of 8		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000295777.9	c.-239G>A		5_prime_UTR_variant	Exon 1 of 9	1		ENSP00000295777.5
SERPINI1	ENST00000446050.7	c.-19+92G>A		intron_variant	Intron 1 of 8	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000472747.2	c.-19+103G>A		intron_variant	Intron 1 of 4	3		ENSP00000420561.2
SERPINI1	ENST00000472941.5	c.-19+590G>A		intron_variant	Intron 1 of 2	3		ENSP00000420133.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0625 AC: 1 AN: 16

Other (OTH) AF: 0.00 AC: 0 AN: 2

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

African (AFR) AF: 0.0926 AC: 3847 AN: 41534

American (AMR) AF: 0.123 AC: 1886 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 420 AN: 3472

East Asian (EAS) AF: 0.0256 AC: 132 AN: 5160

South Asian (SAS) AF: 0.0836 AC: 403 AN: 4822

European-Finnish (FIN) AF: 0.199 AC: 2099 AN: 10572

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15956 AN: 67972

Other (OTH) AF: 0.151 AC: 318 AN: 2112

Alfa AF: 0.173 Hom.: 1476

Bravo AF: 0.154

Asia WGS AF: 0.0580 AC: 201 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cerebral cavernous malformation 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.2
DANN	Benign	0.82
PhyloP100		-0.58
PromoterAI		-0.028	Neutral
Mutation Taster		=277/23	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9835352; hg19: chr3-167453703;