3-167790560-G-T

Position:

• chr3-167790560-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001122752.2(SERPINI1):​c.439G>T​(p.Val147Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,562 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINI1 NM_001122752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.439G>T	p.Val147Leu	missense_variant	3/9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.439G>T	p.Val147Leu	missense_variant	3/9		NP_005016.1
SERPINI1	XM_017006618.3	c.439G>T	p.Val147Leu	missense_variant	3/9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.439G>T	p.Val147Leu	missense_variant	3/9	1	NM_001122752.2	ENSP00000397373.2
SERPINI1	ENST00000295777.9	c.439G>T	p.Val147Leu	missense_variant	3/9	1		ENSP00000295777.5
SERPINI1	ENST00000472747.2	c.439G>T	p.Val147Leu	missense_variant	3/5	3		ENSP00000420561.2
SERPINI1	ENST00000472941.5	c.439G>T	p.Val147Leu	missense_variant	3/3	3		ENSP00000420133.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461562 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.2	.;M;M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.060	T;T;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.96	.;D;D;.
Vest4		0.59, 0.59
MutPred		0.80		Loss of catalytic residue at V147 (P = 0.0291);Loss of catalytic residue at V147 (P = 0.0291);Loss of catalytic residue at V147 (P = 0.0291);Loss of catalytic residue at V147 (P = 0.0291);
MVP		0.72
MPC		0.37
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.62
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs772999261; hg19: chr3-167508348;