rs121909051

Positions:

• 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).

• 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	Protein	UniProt
SERPINI1	NM_001122752.2	c.145T>C	p.Ser49Pro	missense_variant	2/9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.145T>C	p.Ser49Pro	missense_variant	2/9		NP_005016.1
SERPINI1	XM_017006618.3	c.145T>C	p.Ser49Pro	missense_variant	2/9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.145T>C	p.Ser49Pro	missense_variant	2/9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9	c.145T>C	p.Ser49Pro	missense_variant	2/9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2	c.145T>C	p.Ser49Pro	missense_variant	2/5	3		ENSP00000420561.2
SERPINI1	ENST00000472941.5	c.145T>C	p.Ser49Pro	missense_variant	2/3	3		ENSP00000420133.1

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
MutationAssessor	Pathogenic	4.3	.;H;H;.
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;