rs61735309

chr3-167792626-A-G

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.518A>G(p.Asp173Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,613,672 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00047 (4 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.46

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=0.007047981).
• BP6: Variant 3-167792626-A-G is Benign according to our data. Variant chr3-167792626-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 344129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 441 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI1	NM_001122752.2	c.518A>G	p.Asp173Gly	missense_variant	4/9	ENST00000446050.7
SERPINI1	NM_005025.5	c.518A>G	p.Asp173Gly	missense_variant	4/9
SERPINI1	XM_017006618.3	c.518A>G	p.Asp173Gly	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000446050.7	c.518A>G	p.Asp173Gly	missense_variant	4/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9	c.518A>G	p.Asp173Gly	missense_variant	4/9	1		P1
SERPINI1	ENST00000472747.2	c.518A>G	p.Asp173Gly	missense_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 152092 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00538

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00102 AC: 256 AN: 250994 Hom.: 3 AF XY: 0.000877 AC XY: 119 AN XY: 135656

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000465 AC: 680 AN: 1461462 Hom.: 4 Cov.: 31 AF XY: 0.000453 AC XY: 329 AN XY: 727022

Gnomad4 AFR exome AF: 0.00935

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00292 AC: 444 AN: 152210 Hom.: 3 Cov.: 31 AF XY: 0.00305 AC XY: 227 AN XY: 74434

Gnomad4 AFR AF: 0.00809

Gnomad4 AMR AF: 0.00537

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000579 Hom.: 0

Bravo AF: 0.00358

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000955 AC: 116

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial encephalopathy with neuroserpin inclusion bodies Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	16
Dann	Benign	0.14
DEOGEN2	Benign	0.30	T;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.59	D
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.61	N;N;.
MutationTaster	Benign	0.52	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.70	T;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.10
MVP		0.23
MPC		0.12
ClinPred		0.022	T
GERP RS		2.9
Varity_R		0.28
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61735309; hg19: chr3-167510414; COSMIC: COSV99855523; COSMIC: COSV99855523;