chr14-94614679-A-G

Position:

chr14-94614679-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001085.5(SERPINA3):c.238A>G(p.Ile80Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000774 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

SERPINA3
NM_001085.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3156232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA3	NM_001085.5 linkuse as main transcript	c.238A>G	p.Ile80Val	missense_variant	2/5	ENST00000393078.5	NP_001076.2	P01011-1A0A024R6P0
SERPINA3	NM_001384672.1 linkuse as main transcript	c.238A>G	p.Ile80Val	missense_variant	2/5		NP_001371601.1
SERPINA3	NM_001384673.1 linkuse as main transcript	c.238A>G	p.Ile80Val	missense_variant	3/6		NP_001371602.1
SERPINA3	NM_001384674.1 linkuse as main transcript	c.238A>G	p.Ile80Val	missense_variant	3/6		NP_001371603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SERPINA3	ENST00000393078.5 linkuse as main transcript	c.238A>G	p.Ile80Val	missense_variant	2/5	1	NM_001085.5	ENSP00000376793.3	P01011-1
ENSG00000273259	ENST00000553947.1 linkuse as main transcript	n.*1064A>G		non_coding_transcript_exon_variant	5/8	2		ENSP00000452367.2	G3V5I3
ENSG00000273259	ENST00000553947.1 linkuse as main transcript	n.*1064A>G		3_prime_UTR_variant	5/8	2		ENSP00000452367.2	G3V5I3

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251358

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135840

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727248

show subpopulations

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:

0.0000989

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000823

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.40

CADD

Benign

0.0040

DANN

Benign

0.73

DEOGEN2

Benign

0.21

T;T;.;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.75

T;.;T;.

M_CAP

Benign

0.0088

MetaRNN

Benign

0.32

T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.90

L;L;.;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.69

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.32

T;T;T;T

Polyphen

0.58

P;P;.;P

Vest4

0.081

MutPred

0.67

Gain of catalytic residue at A83 (P = 0.002);Gain of catalytic residue at A83 (P = 0.002);Gain of catalytic residue at A83 (P = 0.002);Gain of catalytic residue at A83 (P = 0.002);

MVP

0.42

MPC

0.015

ClinPred

0.089

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.086

gMVP

0.084

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over