3-167790418-T-G

Position:

• chr3-167790418-T-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000446050.7(SERPINI1):​c.297T>G​(p.Ala99=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00055 in 1,613,970 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A99A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: SERPINI1 ENST00000446050.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.451

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-167790418-T-G is Benign according to our data. Variant chr3-167790418-T-G is described in ClinVar as [Benign]. Clinvar id is 466615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-167790418-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.451 with no splicing effect.
• BS2: High AC in GnomAd4 at 440 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINI1	NM_001122752.2	c.297T>G	p.Ala99=	synonymous_variant	3/9	ENST00000446050.7	NP_001116224.1
SERPINI1	NM_005025.5	c.297T>G	p.Ala99=	synonymous_variant	3/9		NP_005016.1
SERPINI1	XM_017006618.3	c.297T>G	p.Ala99=	synonymous_variant	3/9		XP_016862107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINI1	ENST00000446050.7	c.297T>G	p.Ala99=	synonymous_variant	3/9	1	NM_001122752.2	ENSP00000397373	P1
SERPINI1	ENST00000295777.9	c.297T>G	p.Ala99=	synonymous_variant	3/9	1		ENSP00000295777	P1
SERPINI1	ENST00000472747.2	c.297T>G	p.Ala99=	synonymous_variant	3/5	3		ENSP00000420561
SERPINI1	ENST00000472941.5	c.297T>G	p.Ala99=	synonymous_variant	3/3	3		ENSP00000420133

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152226 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

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: 0.00191

GnomAD3 exomes AF: 0.000776 AC: 195 AN: 251376 Hom.: 2 AF XY: 0.000559 AC XY: 76 AN XY: 135848

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000307 AC: 448 AN: 1461626 Hom.: 2 Cov.: 31 AF XY: 0.000246 AC XY: 179 AN XY: 727118

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.000470

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: 0.00000450

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152344 Hom.: 2 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74492

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00141 Hom.: 1

Bravo AF: 0.00326

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial encephalopathy with neuroserpin inclusion bodies Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.39

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: rs61761891; hg19: chr3-167508206;