rs28931569

Positions:

chr14-94383044-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000295.5(SERPINA1):c.194T>C(p.Leu65Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,613,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 2.62

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 Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.796

PP5

Variant 14-94383044-A-G is Pathogenic according to our data. Variant chr14-94383044-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA1	NM_000295.5 linkuse as main transcript	c.194T>C	p.Leu65Pro	missense_variant	2/5	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.194T>C	p.Leu65Pro	missense_variant	2/5	1	NM_000295.5	ENSP00000376802.4		P01009-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251302

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135804

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:

0.0000792

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1460892

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

726524

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000621

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alpha-1-antitrypsin deficiency

Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 19, 2022	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	May 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-1-antitrypsin deficiency (MIM#613490). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 14 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Serpin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as MPorcida allele or Leu41Pro in the literature, it has been reported in alpha-1-antitrypsin deficient patients, including those who were compound heterozygotes with null alleles (PMID: 1975477, 9635295; ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant protein has been showed to have retarded protein folding and were unable to form inhibitory complexes with target protease (PMID: 14767073). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000295.4:c.559A>T; p.(Lys187*)) in a recessive disease. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 65 of the SERPINA1 protein (p.Leu65Pro). This variant is present in population databases (rs28931569, gnomAD 0.009%). This missense change has been observed in individual(s) with alpha 1-antitrypsin deficiency (PMID: 3262617, 9635295). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as M procida and p.Leu41Pro. ClinVar contains an entry for this variant (Variation ID: 17971). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SERPINA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 14767073). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Pathogenic, no assertion criteria provided	curation	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	Reduced enzyme activity -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 05, 2020	- -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 05, 2021

ACMG categories: PM1,PM2,PP3,PP5 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 17, 2017

- -

PI M(PROCIDA)

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

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;D;D;D;D;D;D;D;D;.;.;T;D;.

Eigen

Benign

0.12

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.67

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

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.070

MutationAssessor

Pathogenic

3.6

H;H;H;H;H;H;H;H;H;H;.;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.9

D;D;D;D;D;.;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0020

D;D;D;D;D;.;D;D;D;T;T;T;T;T

Sift4G

Uncertain

0.0040

D;D;D;D;D;.;D;D;D;D;.;.;D;.

Polyphen

0.60

P;P;P;P;P;P;P;P;P;D;.;.;.;.

Vest4

0.54

MVP

1.0

MPC

0.37

ClinPred

0.82

GERP RS

4.8

Varity_R

0.79

gMVP

0.94

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