rs121912714

chr14-94380949-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_000295.5(SERPINA1):c.839A>T(p.Asp280Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 1,614,164 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic,other (★★). Synonymous variant affecting the same amino acid position (i.e. D280D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic; other criteria provided, multiple submitters, no conflicts P:11 O:5
• Conservation: PhyloP100: 1.16

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-94380949-T-A is Pathogenic according to our data. Variant chr14-94380949-T-A is described in ClinVar as [Likely_pathogenic, other]. Clinvar id is 17975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94380949-T-A is described in Lovd as [Likely_benign]. Variant chr14-94380949-T-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.25806603).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.839A>T	p.Asp280Val	missense_variant	3/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.839A>T	p.Asp280Val	missense_variant	3/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000473 AC: 119 AN: 251490 Hom.: 0 AF XY: 0.000478 AC XY: 65 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000545

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000370 AC: 541 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.000353 AC XY: 257 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000337

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74448

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000751 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000818

EpiControl AF: 0.000948

ClinVar

Significance: Pathogenic/Likely pathogenic; other

Submissions summary: Pathogenic:11 Other:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Aug 08, 2022	- -
Likely pathogenic, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 09, 2016	- -
Pathogenic, no assertion criteria provided	curation	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 280 of the SERPINA1 protein (p.Asp280Val). This variant is present in population databases (rs121912714, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with alpha-1 antitrypsin deficiency (AATD) (PMID: 2240842, 2787118, 2831367, 8364590, 15744045, 17906067, 26321041, 27296815). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp256Val, PI*Lowell allele, PI*Duarte allele, or PI*Null Cardiff allele. ClinVar contains an entry for this variant (Variation ID: 17975). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SERPINA1 protein function. Experimental studies have shown that this missense change affects SERPINA1 function (PMID: 2240842, 14767073, 15949707). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Mar 12, 2024	ACMG Criteria: PS3, PS4_M, PM3, PP3, PP5; Individual was compound heterozygous for SERPINA1 variants c.839A>T and c.1096G>A -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 07, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -

not provided Pathogenic:2 Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2016	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SERPINA1 p.Asp280Val variant, often referred to as the Plowell protein variant, was identified in 12 of 248 proband chromosomes (2 homozygotes, frequency: 0.048) from individuals or families with alpha1-antitrypsin deficiency (AATD) and was not identified in 1500 control chromosomes from individuals with normal AAT serum levels (Graham_2015_PMID:26321041; Corda_2011_PMID:21474916; Bornhorst_2007_PMID:17906067). The variant was also identified in dbSNP (ID: rs121912714), LOVD 3.0 and in ClinVar (classified as pathogenic by Trillium Health Partners Credit Valley Hospital, likely pathogenic by Counsyl and CSER_CC_NCGL, University of Washington Medical Center, and 'other' by EGL Genetic Diagnostics). The variant was not identified in Cosmic. The variant was identified in control databases in 129 of 282876 chromosomes at a frequency of 0.000456 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 35 of 10370 chromosomes (freq: 0.003375), Latino in 20 of 35438 chromosomes (freq: 0.000564), Other in 4 of 7226 chromosomes (freq: 0.000554), European (non-Finnish) in 68 of 129190 chromosomes (freq: 0.000526) and South Asian in 2 of 30616 chromosomes (freq: 0.000065); it was not observed in the African, East Asian and European (Finnish) populations. Functional studies of the D280V variant have suggested increased intracellular protein degradation and have demonstrated delayed secretion of the AAT protein, with only the secreted form producing a stable SDS-complex with elastase while the intracellular form demonstrated reduced ability to form a stable complex. However little differences in stability to urea denaturation were observed compared to the wildtype (Ray_2006_PMID: 15949707; Holmes_1990_PMID:2240842). Another functional study found that the D280V variant caused delayed protein folding, however the stability and inhibitory activity of the protein was similar to wildtype once protein folding did occur (Jung_2004_PMID: 14767073). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp280 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2021	Published functional studies demonstrate a damaging effect due to impaired secretion of mutant protein (Holmes et al., 1990; Ray et al., 2005); This variant is associated with the following publications: (PMID: 27535533, 31589614, 31980526, 31447099, 27264265, 26987331, 27296815, 29882371, 2787118, 2240842, 26321041, 17906067, 2831367, 15744045, 2696185, 2606478, 25637381, 1504305, 8364590, 15949707, 21474916, 14767073) -

SERPINA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The SERPINA1 c.839A>T variant is predicted to result in the amino acid substitution p.Asp280Val. This variant has been reported to be causative for autosomal recessive alpha-1-antitrypsin deficiency (Silva et al 2016. PubMed ID: 27296815, reported as p.Asp256Val; Graham et al 2015. PubMed ID: 26321041). This variant is reported in 0.34% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. -

PI Q0(CARDIFF) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

PI NULL(CARDIFF) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

PI P(DUARTE) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

PI P(LOWELL) 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	0.30
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;D;D;D;D;D;D;D;D;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.71	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	0.78	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-7.2	D;D;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.049	D;D;D;D;D;.;D;D;D;T
Polyphen		0.98	D;D;D;D;D;D;D;D;D;P
Vest4		0.79
MVP		0.94
MPC		0.34
ClinPred		0.22	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.71
gMVP		0.64

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

Other links and lift over

dbSNP: rs121912714; hg19: chr14-94847286;