3-167735251-T-C

Variant names:

• chr3-167735251-T-C
• rs9853967
• ENST00000472941.5:c.-93T>C

Variant summary

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

The ENST00000472941.5(SERPINI1):​c.-93T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 152,284 control chromosomes in the GnomAD database, including 26,532 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (26503 hom., cov: 32)
  • Exomes 𝑓: 0.44 (29 hom.)
• Consequence: SERPINI1 ENST00000472941.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.84
• Publications: 3 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=-0.8).
• BP6: Variant 3-167735251-T-C is Benign according to our data. Variant chr3-167735251-T-C is described in ClinVar as [Benign]. Clinvar id is 1168304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000472941.5	c.-93T>C		5_prime_UTR_variant	Exon 1 of 3	3		ENSP00000420133.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84830 AN: 151862 Hom.: 26447 Cov.: 32

Gnomad AFR AF: 0.847

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.351

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.334

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.438 AC: 133 AN: 304 Hom.: 29 Cov.: 0 AF XY: 0.448 AC XY: 104 AN XY: 232

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AF: 0.167 AC: 1 AN: 6

South Asian (SAS) AF: 0.400 AC: 4 AN: 10

European-Finnish (FIN) AF: 0.583 AC: 7 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.424 AC: 106 AN: 250

Other (OTH) AF: 0.786 AC: 11 AN: 14

GnomAD4 genome AF: 0.559 AC: 84924 AN: 151980 Hom.: 26503 Cov.: 32 AF XY: 0.550 AC XY: 40890 AN XY: 74280

African (AFR) AF: 0.847 AC: 35135 AN: 41478

American (AMR) AF: 0.359 AC: 5479 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1186 AN: 3470

East Asian (EAS) AF: 0.349 AC: 1791 AN: 5138

South Asian (SAS) AF: 0.349 AC: 1681 AN: 4818

European-Finnish (FIN) AF: 0.531 AC: 5602 AN: 10556

Middle Eastern (MID) AF: 0.339 AC: 99 AN: 292

European-Non Finnish (NFE) AF: 0.480 AC: 32582 AN: 67934

Other (OTH) AF: 0.462 AC: 974 AN: 2106

Alfa AF: 0.541 Hom.: 2993

Bravo AF: 0.557

Asia WGS AF: 0.392 AC: 1366 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Familial encephalopathy with neuroserpin inclusion bodies Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.80
CADD	Benign	0.52
DANN	Benign	0.73
PhyloP100		-2.8
PromoterAI		-0.039	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9853967; hg19: chr3-167453039;