Genetic Variant SERPINA3:p.Phe86Leu (chr14-94614699-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001085.5(SERPINA3):c.258C>A(p.Phe86Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F86F) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SERPINA3
NM_001085.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.34

Publications

2 publications found

Variant links:

Genes affected

SERPINA3 (HGNC:16): (serpin family A member 3) The protein encoded by this gene is a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. This gene is one in a cluster of serpin genes located on the q arm of chromosome 14. Polymorphisms in this protein appear to be tissue specific and influence protease targeting. Variations in this protein's sequence have been implicated in Alzheimer's disease, and deficiency of this protein has been associated with liver disease. Mutations have been identified in patients with Parkinson disease and chronic obstructive pulmonary disease. [provided by RefSeq, Jun 2020]

SERPINA3 links:

ENSG00000273259 (HGNC:):

ENSG00000273259 links:

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ACMG classification

Classification was made for transcript

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=0.22494361).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINA3	NM_001085.5	MANE Select	c.258C>A	p.Phe86Leu	missense	Exon 2 of 5	NP_001076.2	P01011-1
SERPINA3	NM_001384672.1		c.258C>A	p.Phe86Leu	missense	Exon 2 of 5	NP_001371601.1	P01011-1
SERPINA3	NM_001384673.1		c.258C>A	p.Phe86Leu	missense	Exon 3 of 6	NP_001371602.1	P01011-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SERPINA3	ENST00000393078.5	TSL:1 MANE Select	c.258C>A	p.Phe86Leu	missense	Exon 2 of 5	ENSP00000376793.3	P01011-1
SERPINA3	ENST00000393080.8	TSL:1	c.258C>A	p.Phe86Leu	missense	Exon 2 of 5	ENSP00000376795.4	P01011-1
ENSG00000273259	ENST00000553947.1	TSL:2	n.*1084C>A		non_coding_transcript_exon	Exon 5 of 8	ENSP00000452367.2	G3V5I3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251352

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.19

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.60

M_CAP

Benign

0.017

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.20

PhyloP100

1.3

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.6

REVEL

Benign

0.20

Sift

Benign

0.91

Sift4G

Benign

1.0

Polyphen

0.0070

Vest4

0.045

MutPred

0.53

Gain of catalytic residue at S81 (P = 6e-04)

MVP

0.69

MPC

0.011

ClinPred

0.10

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.45

gMVP

0.13

Mutation Taster

=53/47

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over