rs17580

Variant names:

• chr14-94380925-T-A
• rs17580
• NM_000295.5:c.863A>T
• SERPINA1 p.Glu288Val

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 13P and 8B. PS3 PP3 PP5_Very_Strong BA1

The NM_000295.5(SERPINA1):​c.863A>T​(p.Glu288Val) variant causes a missense change. The variant allele was found at a frequency of 0.0364 in 1,614,182 control chromosomes in the GnomAD database, including 1,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic low penetrance,other (★★). ClinVar reports functional evidence for this variant: "SCV000389650: Curiel et al. (1989) demonstrated that the p.Glu288Val variant results in intracellular degradation of AAT protein prior to secretion." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (106 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1236 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Pathogenic/Pathogenic, low penetrance; other criteria provided, multiple submitters, no conflicts P:28 U:1 O:7
• Conservation: PhyloP100: 6.46
• Publications: 172 publications found

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, PanelApp Australia, 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000389650: Curiel et al. (1989) demonstrated that the p.Glu288Val variant results in intracellular degradation of AAT protein prior to secretion.; SCV000538062: The S allele has been shown to cause reduced cellular secretion of alpha 1AT because the newly synthesized S-type alpha 1AT protein is degraded intracellularly prior to secretion (Curiel et al., 1989).; SCV000630393: Experimental studies have shown that this variant results in reduced secretion of alpha-1 antitrypsin due to intracellular degradation in vitro (PMID: 2567291), and causes lower expression as well as secretion in blood (PMID: 2567291, 22426792).; SCV002556452: "Well-established functional studies show a deleterious effect of this variant" (PMID:2567291); SCV002768380: The S allele has previously been shown to result in intracellular protein degradation (PMID: 15978931). (SP); SCV003844608: Experimental studies have shown this variant to result in reduced secretion of alpha-1 antitrypsin due to intracellular degradation in vitro, which causes lower expression as well as secretion in blood (Curiel_1999).; SCV004812555: In silico modelling and in vitro assays using human blood monocytes and mouse fibroblasts showed that the mutant protein is more susceptible to intracellular polymerisation and degradation leading to reduced secretion when compared to the wildtype protein; PMID:3257660; SCV000568767: Results in reduced cellular secretion of alpha-1 antitrypsin as the S-type alpha-1 antitrypsin protein is degraded intracellularly prior to secretion (Curiel et al., 1989; Ferrarotti et al., 2012); SCV001552729: Functional studies of the variant have shown to cause reduced secretion of alpha-1 antitrypsin due to intracellular degradation in vitro and to cause lower expression as well as secretion of alpha-1 antitrypsin in blood samples (Curiel_1989_PMID: 2567291; Ferraroti_2012_PMID:22426792).; SCV002688491: "In vitro studies demonstrate that this mutant allele results in reduced AAT levels due to intracellular degradation and decreased secretion of the protein (Curiel, 1989)."
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 14-94380925-T-A is Pathogenic according to our data. Variant chr14-94380925-T-A is described in ClinVar as Pathogenic/Pathogenic,_low_penetrance|other. ClinVar VariationId is 17969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	NM_000295.5	MANE Select	c.863A>T	p.Glu288Val	missense	Exon 3 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.863A>T	p.Glu288Val	missense	Exon 3 of 5	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.863A>T	p.Glu288Val	missense	Exon 5 of 7	NP_001002236.1	E9KL23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.863A>T	p.Glu288Val	missense	Exon 3 of 5	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.863A>T	p.Glu288Val	missense	Exon 3 of 5	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000393088.8	TSL:1	c.863A>T	p.Glu288Val	missense	Exon 5 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4376 AN: 152202 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.00880

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0553

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00828

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0468

GnomAD2 exomes AF: 0.0233 AC: 5859 AN: 251480 AF XY: 0.0233

Gnomad AFR exome AF: 0.00794

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00845

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0372 AC: 54315 AN: 1461862 Hom.: 1236 Cov.: 31 AF XY: 0.0360 AC XY: 26152 AN XY: 727236

African (AFR) AF: 0.00642 AC: 215 AN: 33480

American (AMR) AF: 0.0323 AC: 1443 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0140 AC: 366 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00841 AC: 449 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0448 AC: 49871 AN: 1111986

Other (OTH) AF: 0.0324 AC: 1956 AN: 60390

GnomAD4 genome AF: 0.0287 AC: 4376 AN: 152320 Hom.: 106 Cov.: 32 AF XY: 0.0275 AC XY: 2046 AN XY: 74486

African (AFR) AF: 0.00878 AC: 365 AN: 41590

American (AMR) AF: 0.0552 AC: 844 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00828 AC: 88 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0416 AC: 2830 AN: 68008

Other (OTH) AF: 0.0464 AC: 98 AN: 2114

Alfa AF: 0.0340 Hom.: 38

Bravo AF: 0.0325

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0351

EpiControl AF: 0.0392

ClinVar

ClinVar submissions

Significance: Pathogenic/Pathogenic, low penetrance; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	Alpha-1-antitrypsin deficiency (20)
7	-	-	not provided (8)
1	-	-	Autosomal recessive SERPINA1-related disorders (1)
1	-	-	Chronic obstructive pulmonary disease;C0221757:Alpha-1-antitrypsin deficiency (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
1	-	-	SERPINA1-related disorder (1)
-	-	-	Cystic fibrosis (1)
-	-	-	PI S (1)
-	-	-	Susceptibility to severe coronavirus disease (COVID-19) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0055	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		6.5
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.74
Mutation Taster		=28/72	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.69		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs17580;

hg19: chr14-94847262;

COSMIC: COSV63345500;

COSMIC: COSV63345500;