rs762427588

Variant names:

• chr3-167792634-A-C
• rs762427588
• NM_001122752.2:c.526A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-167792634-A-C
• chr3-167792634-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001122752.2(SERPINI1):​c.526A>C​(p.Thr176Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T176A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.94
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.526A>C	p.Thr176Pro	missense_variant	Exon 4 of 9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.526A>C	p.Thr176Pro	missense_variant	Exon 4 of 9		NP_005016.1
SERPINI1	XM_017006618.3	c.526A>C	p.Thr176Pro	missense_variant	Exon 4 of 9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.526A>C	p.Thr176Pro	missense_variant	Exon 4 of 9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9	c.526A>C	p.Thr176Pro	missense_variant	Exon 4 of 9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2	c.526A>C	p.Thr176Pro	missense_variant	Exon 4 of 5	3		ENSP00000420561.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461516 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727052

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44634

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.9	H;H;.
PhyloP100		8.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.77
MutPred		0.88		Loss of glycosylation at T176 (P = 0.2929);Loss of glycosylation at T176 (P = 0.2929);Loss of glycosylation at T176 (P = 0.2929);
MVP		0.93
MPC		0.55
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.88
Mutation Taster		=9/91	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: rs762427588; hg19: chr3-167510422;