3-167794703-A-C

Variant names:

• chr3-167794703-A-C
• rs1553774956
• NM_001122752.2:c.760A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001122752.2(SERPINI1):​c.760A>C​(p.Met254Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M254T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.09
• 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, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000287319 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36311784).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122752.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINI1	NM_001122752.2	MANE Select	c.760A>C	p.Met254Leu	missense	Exon 5 of 9	NP_001116224.1	A0A0S2Z455
	SERPINI1	NM_005025.5		c.760A>C	p.Met254Leu	missense	Exon 5 of 9	NP_005016.1	A0A0S2Z455

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINI1	ENST00000446050.7	TSL:1 MANE Select	c.760A>C	p.Met254Leu	missense	Exon 5 of 9	ENSP00000397373.2	Q99574
	SERPINI1	ENST00000295777.9	TSL:1	c.760A>C	p.Met254Leu	missense	Exon 5 of 9	ENSP00000295777.5	Q99574
	SERPINI1	ENST00000872947.1		c.760A>C	p.Met254Leu	missense	Exon 5 of 9	ENSP00000543006.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial encephalopathy with neuroserpin inclusion bodies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.067
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.23	N
PhyloP100		7.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.64	N
REVEL	Uncertain	0.41
Sift	Benign	0.98	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.60
MutPred		0.53		Loss of sheet (P = 0.1398)
MVP		0.64
MPC		0.085
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.37
Mutation Taster		=36/64	disease causing

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: rs1553774956; hg19: chr3-167512491;