Genetic Variant NM_000295.5:c.1145T>G (chr14-94378561-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_000295.5(SERPINA1):c.1145T>G(p.Met382Arg) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:3

Conservation

PhyloP100: 0.730

Publications

10 publications found

Variant links:

Genes affected

SERPINA1 (HGNC:8941): (serpin family A member 1) The protein encoded by this gene is a serine protease inhibitor belonging to the serpin superfamily whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. This protein is produced in the liver, the bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut. Defects in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

SERPINA1 Gene-Disease associations (from GenCC):

alpha 1-antitrypsin deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cystic fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SERPINA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-94378561-A-C is Pathogenic according to our data. Variant chr14-94378561-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 17982.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.27427423). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000295.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SERPINA1	NM_000295.5	MANE Select	c.1145T>G	p.Met382Arg	missense	Exon 5 of 5	NP_000286.3
SERPINA1	NM_001002235.3		c.1145T>G	p.Met382Arg	missense	Exon 5 of 5	NP_001002235.1
SERPINA1	NM_001002236.3		c.1145T>G	p.Met382Arg	missense	Exon 7 of 7	NP_001002236.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.1145T>G	p.Met382Arg	missense	Exon 5 of 5	ENSP00000376802.4
SERPINA1	ENST00000355814.8	TSL:1	c.1145T>G	p.Met382Arg	missense	Exon 5 of 5	ENSP00000348068.4
SERPINA1	ENST00000393088.8	TSL:1	c.1145T>G	p.Met382Arg	missense	Exon 7 of 7	ENSP00000376803.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Alpha-1-antitrypsin deficiency

Pathogenic:2

Dec 08, 2014

Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

May 01, 2014

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

Pathogenic:1

Apr 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

8.3

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.26

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.67

M_CAP

Benign

0.034

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.1

PhyloP100

0.73

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.51

Sift

Benign

0.23

Sift4G

Benign

0.27

Polyphen

0.019

Vest4

0.53

MutPred

0.72

Gain of catalytic residue at P385 (P = 2e-04)

MVP

0.70

MPC

0.061

ClinPred

0.11

GERP RS

-9.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.71

gMVP

0.73

Mutation Taster

=0/100

disease causing (ClinVar)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over