14-94378506-T-G

Position:

chr14-94378506-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000295.5(SERPINA1):c.1200A>C(p.Glu400Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,613,760 control chromosomes in the GnomAD database, including 57,937 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4621 hom., cov: 32)

Exomes 𝑓: 0.26 ( 53316 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -2.75

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.7135353E-4).

BP6

Variant 14-94378506-T-G is Benign according to our data. Variant chr14-94378506-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 17958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94378506-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA1	NM_000295.5 linkuse as main transcript	c.1200A>C	p.Glu400Asp	missense_variant	5/5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9 linkuse as main transcript	c.1200A>C	p.Glu400Asp	missense_variant	5/5	1	NM_000295.5	ENSP00000376802.4		P01009-1

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34671

AN:

151882

Hom.:

4601

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.138

Gnomad AMR

AF:

0.333

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.298

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.315

Gnomad NFE

AF:

0.253

Gnomad OTH

AF:

0.240

GnomAD3 exomes

AF:

0.277

AC:

69749

AN:

251452

Hom.:

10408

AF XY:

0.287

AC XY:

39006

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.322

Gnomad ASJ exome

AF:

0.266

Gnomad EAS exome

AF:

0.284

Gnomad SAS exome

AF:

0.425

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.275

GnomAD4 exome

AF:

0.265

AC:

387193

AN:

1461760

Hom.:

53316

Cov.:

AF XY:

0.270

AC XY:

196696

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.103

Gnomad4 AMR exome

AF:

0.326

Gnomad4 ASJ exome

AF:

0.265

Gnomad4 EAS exome

AF:

0.286

Gnomad4 SAS exome

AF:

0.421

Gnomad4 FIN exome

AF:

0.241

Gnomad4 NFE exome

AF:

0.255

Gnomad4 OTH exome

AF:

0.268

GnomAD4 genome

AF:

0.228

AC:

34717

AN:

152000

Hom.:

4621

Cov.:

AF XY:

0.235

AC XY:

17427

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.112

Gnomad4 AMR

AF:

0.333

Gnomad4 ASJ

AF:

0.268

Gnomad4 EAS

AF:

0.298

Gnomad4 SAS

AF:

0.433

Gnomad4 FIN

AF:

0.235

Gnomad4 NFE

AF:

0.253

Gnomad4 OTH

AF:

0.245

Alfa

AF:

0.245

Hom.:

9721

Bravo

AF:

0.223

TwinsUK

AF:

0.251

AC:

931

ALSPAC

AF:

0.250

AC:

963

ESP6500AA

AF:

0.107

AC:

472

ESP6500EA

AF:

0.258

AC:

2222

ExAC

AF:

0.275

AC:

33350

Asia WGS

AF:

0.336

AC:

1169

AN:

3478

EpiCase

AF:

0.259

EpiControl

AF:

0.263

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2013	Benign based on MAF in ESP (10.71% in AA, 25.84% in EA) -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2023	- -

Alpha-1-antitrypsin deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	curation	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2020	This variant is associated with the following publications: (PMID: 32427833) -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2016

This alteration is classified as 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. -

PI M3

Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.0010

DANN

Benign

0.11

DEOGEN2

Benign

0.12

T;T;T;T;T;T;T;T;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.31

.;.;.;T;.;.;.;.;.

MetaRNN

Benign

0.00047

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.58

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

1.5

N;N;N;N;N;.;N;N;N

REVEL

Benign

0.18

Sift

Benign

1.0

T;T;T;T;T;.;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;.;T;T;T

Polyphen

0.0

B;B;B;B;B;B;B;B;B

Vest4

0.036

MutPred

0.35

Gain of catalytic residue at Q401 (P = 9e-04);Gain of catalytic residue at Q401 (P = 9e-04);Gain of catalytic residue at Q401 (P = 9e-04);Gain of catalytic residue at Q401 (P = 9e-04);Gain of catalytic residue at Q401 (P = 9e-04);Gain of catalytic residue at Q401 (P = 9e-04);Gain of catalytic residue at Q401 (P = 9e-04);Gain of catalytic residue at Q401 (P = 9e-04);Gain of catalytic residue at Q401 (P = 9e-04);

MPC

0.042

ClinPred

0.015

GERP RS

-9.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.29

gMVP

0.37

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