NM_001122752.2:c.1183A>G

Variant names:

• chr3-167825273-A-G
• rs144637103
• NM_001122752.2:c.1183A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_001122752.2(SERPINI1):​c.1183A>G​(p.Met395Val) variant causes a missense change. The variant allele was found at a frequency of 0.000116 in 1,613,486 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M395L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.42
• Publications: 1 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001122752.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.05598384).
• BP6: Variant 3-167825273-A-G is Benign according to our data. Variant chr3-167825273-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 344133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 63 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.1183A>G	p.Met395Val	missense	Exon 9 of 9	NP_001116224.1	A0A0S2Z455
	SERPINI1	NM_005025.5		c.1183A>G	p.Met395Val	missense	Exon 9 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.1183A>G	p.Met395Val	missense	Exon 9 of 9	ENSP00000397373.2	Q99574
	SERPINI1	ENST00000295777.9	TSL:1	c.1183A>G	p.Met395Val	missense	Exon 9 of 9	ENSP00000295777.5	Q99574
	SERPINI1	ENST00000872947.1		c.1183A>G	p.Met395Val	missense	Exon 9 of 9	ENSP00000543006.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000119 AC: 30 AN: 251398 AF XY: 0.000110

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000849 AC: 124 AN: 1461152 Hom.: 0 Cov.: 29 AF XY: 0.0000908 AC XY: 66 AN XY: 726930

African (AFR) AF: 0.00197 AC: 66 AN: 33462

American (AMR) AF: 0.000112 AC: 5 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111410

Other (OTH) AF: 0.000282 AC: 17 AN: 60366

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74494

African (AFR) AF: 0.00132 AC: 55 AN: 41578

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000187 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial encephalopathy with neuroserpin inclusion bodies (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.82	L
PhyloP100		5.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.52
Sift	Benign	0.18	T
Sift4G	Benign	0.16	T
Polyphen		0.97	D
Vest4		0.52
MVP		0.59
MPC		0.27
ClinPred		0.047	T
GERP RS		4.5
Varity_R		0.58
gMVP		0.57
Mutation Taster		=59/41	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: rs144637103; hg19: chr3-167543061;