3-167789168-A-C

Variant names:

• chr3-167789168-A-C
• rs61735307
• NM_001122752.2:c.40A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122752.2(SERPINI1):​c.40A>C​(p.Ser14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. S14G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.76
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22877854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.40A>C	p.Ser14Arg	missense_variant	Exon 2 of 9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.40A>C	p.Ser14Arg	missense_variant	Exon 2 of 9		NP_005016.1
SERPINI1	XM_017006618.3	c.40A>C	p.Ser14Arg	missense_variant	Exon 2 of 9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.40A>C	p.Ser14Arg	missense_variant	Exon 2 of 9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9	c.40A>C	p.Ser14Arg	missense_variant	Exon 2 of 9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2	c.40A>C	p.Ser14Arg	missense_variant	Exon 2 of 5	3		ENSP00000420561.2
SERPINI1	ENST00000472941.5	c.40A>C	p.Ser14Arg	missense_variant	Exon 2 of 3	3		ENSP00000420133.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.029	T;T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.53	T;.;T;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.8	.;L;L;.
PhyloP100		2.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.013	D;T;T;T
Polyphen		0.45	.;P;P;.
Vest4		0.48, 0.48
MutPred		0.41		Loss of catalytic residue at L10 (P = 0.1029);Loss of catalytic residue at L10 (P = 0.1029);Loss of catalytic residue at L10 (P = 0.1029);Loss of catalytic residue at L10 (P = 0.1029);
MVP		0.48
MPC		0.18
ClinPred		0.68	D
GERP RS		4.1
Varity_R		0.16
gMVP		0.51
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61735307; hg19: chr3-167506956;