3-167794781-G-T

Variant names:

• chr3-167794781-G-T
• rs55872908
• NM_001122752.2:c.838G>T
• SERPINI1 p.Ala280Ser

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001122752.2(SERPINI1):​c.838G>T​(p.Ala280Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A280T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.66
• Publications: 9 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000287319 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32601893).
• BS2: High AC in GnomAdExome4 at 27 AD gene.

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.838G>T	p.Ala280Ser	missense	Exon 5 of 9	NP_001116224.1	A0A0S2Z455
	SERPINI1	NM_005025.5		c.838G>T	p.Ala280Ser	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.838G>T	p.Ala280Ser	missense	Exon 5 of 9	ENSP00000397373.2	Q99574
	SERPINI1	ENST00000295777.9	TSL:1	c.838G>T	p.Ala280Ser	missense	Exon 5 of 9	ENSP00000295777.5	Q99574
	SERPINI1	ENST00000872947.1		c.838G>T	p.Ala280Ser	missense	Exon 5 of 9	ENSP00000543006.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461378 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726976

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1111780

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 58

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial encephalopathy with neuroserpin inclusion bodies (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.071	D
MutationAssessor	Benign	1.2	L
PhyloP100		7.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.030	N
REVEL	Uncertain	0.47
Sift	Benign	0.63	T
Sift4G	Benign	0.56	T
Varity_R		0.73
gMVP		0.34
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs55872908;

hg19: chr3-167512569;