3-167790410-G-C

Variant names:

• chr3-167790410-G-C
• rs61750375
• NM_001122752.2:c.289G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001122752.2(SERPINI1):​c.289G>C​(p.Val97Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V97I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05329287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.289G>C	p.Val97Leu	missense_variant	Exon 3 of 9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.289G>C	p.Val97Leu	missense_variant	Exon 3 of 9		NP_005016.1
SERPINI1	XM_017006618.3	c.289G>C	p.Val97Leu	missense_variant	Exon 3 of 9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.289G>C	p.Val97Leu	missense_variant	Exon 3 of 9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9	c.289G>C	p.Val97Leu	missense_variant	Exon 3 of 9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2	c.289G>C	p.Val97Leu	missense_variant	Exon 3 of 5	3		ENSP00000420561.2
SERPINI1	ENST00000472941.5	c.289G>C	p.Val97Leu	missense_variant	Exon 3 of 3	3		ENSP00000420133.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461550 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727088

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111782

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	4.4
DANN	Benign	0.85
DEOGEN2	Benign	0.064	T;T;T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.55	T;.;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.053	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	.;N;N;.
PhyloP100		1.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.1	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.38	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.20
MutPred		0.51		Loss of methylation at K100 (P = 0.0864);Loss of methylation at K100 (P = 0.0864);Loss of methylation at K100 (P = 0.0864);Loss of methylation at K100 (P = 0.0864);
MVP		0.54
MPC		0.089
ClinPred		0.042	T
GERP RS		3.4
Varity_R		0.15
gMVP		0.26
Mutation Taster		=95/5	polymorphism

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: rs61750375; hg19: chr3-167508198;