Variant chr14-94614635-T-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001085.5(SERPINA3):c.194T>G(p.Val65Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SERPINA3
NM_001085.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.860

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:

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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/exons	MANE
SERPINA3	NM_001085.5 linkuse as main transcript	c.194T>G	p.Val65Gly	missense_variant	2/5	ENST00000393078.5
SERPINA3	NM_001384672.1 linkuse as main transcript	c.194T>G	p.Val65Gly	missense_variant	2/5
SERPINA3	NM_001384673.1 linkuse as main transcript	c.194T>G	p.Val65Gly	missense_variant	3/6
SERPINA3	NM_001384674.1 linkuse as main transcript	c.194T>G	p.Val65Gly	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA3	ENST00000393078.5 linkuse as main transcript	c.194T>G	p.Val65Gly	missense_variant	2/5	1	NM_001085.5	P1	P01011-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727246

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

The c.194T>G (p.V65G) alteration is located in exon 2 (coding exon 1) of the SERPINA3 gene. This alteration results from a T to G substitution at nucleotide position 194, causing the valine (V) at amino acid position 65 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

T;T;.;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.16

T;.;T;.

M_CAP

Benign

0.072

MetaRNN

Uncertain

0.71

D;D;D;D

MetaSVM

Benign

-0.39

MutationAssessor

Benign

0.77

N;N;.;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.96

D;D;.;D

Vest4

0.16

MutPred

0.75

Loss of stability (P = 0.0024);Loss of stability (P = 0.0024);Loss of stability (P = 0.0024);Loss of stability (P = 0.0024);

MVP

0.73

MPC

0.053

ClinPred

0.64

GERP RS

0.87

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.57

gMVP

0.14

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over