rs11547811

chr3-167789336-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.208A>G(p.Lys70Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,614,196 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00073 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.13

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=0.010646611).
• BP6: Variant 3-167789336-A-G is Benign according to our data. Variant chr3-167789336-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 466613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI1	NM_001122752.2	c.208A>G	p.Lys70Glu	missense_variant	2/9	ENST00000446050.7
SERPINI1	NM_005025.5	c.208A>G	p.Lys70Glu	missense_variant	2/9
SERPINI1	XM_017006618.3	c.208A>G	p.Lys70Glu	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000446050.7	c.208A>G	p.Lys70Glu	missense_variant	2/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9	c.208A>G	p.Lys70Glu	missense_variant	2/9	1		P1
SERPINI1	ENST00000472747.2	c.208A>G	p.Lys70Glu	missense_variant	2/5	3
SERPINI1	ENST00000472941.5	c.208A>G	p.Lys70Glu	missense_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152248 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000255 AC: 64 AN: 251238 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135814

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000848 AC: 124 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.0000729 AC XY: 53 AN XY: 727212

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152366 Hom.: 1 Cov.: 33 AF XY: 0.000590 AC XY: 44 AN XY: 74516

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000206 Hom.: 1

Bravo AF: 0.000737

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000264 AC: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial encephalopathy with neuroserpin inclusion bodies Benign:2

Likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.080	T;T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.71	T;.;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.78	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.067	T;T;T;T
Polyphen		0.0010	.;B;B;.
Vest4		0.20, 0.20
MVP		0.26
MPC		0.13
ClinPred		0.022	T
GERP RS		5.2
Varity_R		0.39
gMVP		0.38

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: rs11547811; hg19: chr3-167507124;