rs121909051

chr3-167789273-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001122752.2(SERPINI1):c.145T>C(p.Ser49Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S49S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.15

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 3-167789273-T-C is Pathogenic according to our data. Variant chr3-167789273-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7086.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINI1	NM_001122752.2	c.145T>C	p.Ser49Pro	missense_variant	2/9	ENST00000446050.7
SERPINI1	NM_005025.5	c.145T>C	p.Ser49Pro	missense_variant	2/9
SERPINI1	XM_017006618.3	c.145T>C	p.Ser49Pro	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINI1	ENST00000446050.7	c.145T>C	p.Ser49Pro	missense_variant	2/9	1	NM_001122752.2	P1
SERPINI1	ENST00000295777.9	c.145T>C	p.Ser49Pro	missense_variant	2/9	1		P1
SERPINI1	ENST00000472747.2	c.145T>C	p.Ser49Pro	missense_variant	2/5	3
SERPINI1	ENST00000472941.5	c.145T>C	p.Ser49Pro	missense_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial encephalopathy with neuroserpin inclusion bodies Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 02, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D;D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.90
MutPred		0.95		Gain of glycosylation at P50 (P = 0.153);Gain of glycosylation at P50 (P = 0.153);Gain of glycosylation at P50 (P = 0.153);Gain of glycosylation at P50 (P = 0.153);
MVP		0.95
MPC		0.54
ClinPred		1.0	D
GERP RS		5.2
Varity_R		1.0
gMVP		0.95

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: rs121909051; hg19: chr3-167507061;