Genetic Variant NM_001085.5:c.238A>C (chr14-94614679-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001085.5(SERPINA3):c.238A>C(p.Ile80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SERPINA3
NM_001085.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.532

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 made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA3	NM_001085.5 link	c.238A>C	p.Ile80Leu	missense_variant	Exon 2 of 5	ENST00000393078.5	NP_001076.2	P01011-1A0A024R6P0
SERPINA3	NM_001384672.1 link	c.238A>C	p.Ile80Leu	missense_variant	Exon 2 of 5		NP_001371601.1
SERPINA3	NM_001384673.1 link	c.238A>C	p.Ile80Leu	missense_variant	Exon 3 of 6		NP_001371602.1
SERPINA3	NM_001384674.1 link	c.238A>C	p.Ile80Leu	missense_variant	Exon 3 of 6		NP_001371603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINA3	ENST00000393078.5 link	c.238A>C	p.Ile80Leu	missense_variant	Exon 2 of 5	1	NM_001085.5	ENSP00000376793.3	P01011-1
ENSG00000273259	ENST00000553947.1 link	n.*1064A>C		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000452367.2	G3V5I3
ENSG00000273259	ENST00000553947.1 link	n.*1064A>C		3_prime_UTR_variant	Exon 5 of 8	2		ENSP00000452367.2	G3V5I3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.29

CADD

Benign

1.3

DANN

Benign

0.97

DEOGEN2

Benign

0.31

T;T;.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.71

T;.;T;.

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.7

L;L;.;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Uncertain

0.42

Sift

Uncertain

0.024

D;D;D;D

Sift4G

Uncertain

0.034

D;D;D;D

Polyphen

0.17

B;B;.;B

Vest4

0.23

MutPred

0.68

Gain of catalytic residue at S81 (P = 0.0018);Gain of catalytic residue at S81 (P = 0.0018);Gain of catalytic residue at S81 (P = 0.0018);Gain of catalytic residue at S81 (P = 0.0018);

MVP

0.57

MPC

0.034

ClinPred

0.39

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over