14-94378610-C-T

Variant names:

• chr14-94378610-C-T
• rs28929474
• NM_000295.5:c.1096G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PS3 PM5 PP5 BP4

The NM_000295.5(SERPINA1):​c.1096G>A​(p.Glu366Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0159 in 1,614,142 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). ClinVar reports functional evidence for this variant: "SCV000389647: "At least three studies have demonstrated that the low levels of serum AAT are a result of the p.Glu366Lys variant causing an accumulation of the protein in the endoplasmic reticulum of the hepatocyte with subsequent damage to the cells leading to liver disease (Dycaico et al. 1988" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E366G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.012 (46 hom., cov: 33)
  • Exomes 𝑓: 0.016 (217 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications P:46 U:2 O:5
• Conservation: PhyloP100: 5.27
• Publications: 543 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000389647: "At least three studies have demonstrated that the low levels of serum AAT are a result of the p.Glu366Lys variant causing an accumulation of the protein in the endoplasmic reticulum of the hepatocyte with subsequent damage to the cells leading to liver disease (Dycaico et al. 1988; Lomas et al. 1992; Hughes et al. 2014)."; SCV000630386: Experimental studies have shown that this missense change is five times less effective than the normal M allele as an inhibitor of neutrophil elastase and it forms polymers in the lung that can be chemoattractants for neutrophils, thereby increasing inflammation (PMID: 3500183, 9569237, 12034572). It has also been shown to alter the SERPINA1 protein natural conformation thereby contributing to the formation of polymers (PMID: 22735536, 25181470).; SCV001142445: Functional studies demonstrate that that this variant plays as an inhibitor of neutrophil elastase and it forms polymers in the lung (PMID: 9569237), and alters the global structural dynamics of alpha-1-Antitrypsin (PMID: 25181470).; SCV002061259: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 2904702, PMID: 19398551; PMID: 3500183) - PS3_supporting."; SCV002572444: Several publications reported loss-of-function mechanism for the variant, i.e., homozygous individuals have a serum concentration of alpha-1 antitrypsin (AAT) that is approximately 10%-20% of normal, and the ability of the variant protein to inhibit neutrophil elastase is also decreased (e.g., Ogushi_1987, Bornhorst_2013). Studies also demonstrated that the variant protein can form (toxic) intracellular aggregates, and extracellular polymers with chemotactic properties for neutrophils, resulting in an exacerbated proinflammatory phenotype, especially in response to cigarette smoke (e.g., Elliott_1998, Parmar_2002, Alam_2014). PMID: 24592811, 32699024, 23632999, 1889260, 9569237, 22426792, 27246852, 25181470, 3500183, 12034572, 34408828, 20301692, 15978931, 34408829, 22933512, 35263815; SCV003920463: "In addition, functional studies have shown that this variant leads to misfolding and accumulation of protein in hepatocyte endoplasmic reticulum." (Pan 2009 PMID:19444872, Kass 2012 PMID:22735536, Hughes 2013 PMID:25181470).; SCV004177078: "In support of this prediction, functional studies show this variant leads to an accumulation of the protein leading to liver damage, indicating that this variant impacts protein function (Dycaico MJ et al., PMID: 3264419; Lomas DA et al., PMID: 1608473)."; SCV006585541: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product." PMID:25181470; SCV000321941: Published functional studies demonstrate that the E366K variant removes a salt bridge to Lys290 and a hydrogen bond to Thr203, causing misfolding of the protein within the endoplasmic reticulum, which results in a lack of secretion from hepatocytes and a reduction of plasma AAT levels to 10-15% of normal (PMID: 25181470); SCV001553787: However, functional studies have demonstrated that the PI*Z variant disrupts the native structure of the protein and results in increased polymerization and lack of functional protein (Hughes_2014_PMID:25181470; Lomas_1992_PMID:1608473).; SCV000740918: "The resulting mutant protein polymerizes and aggregates in the endoplasmic reticulum of hepatocytes; in addition, the polymerized protein is resistant to degradation (Carrell RW et al. N. Engl. J. Med., 2002 Jan;346:45-53)."; SCV002495950: "In addition, functional studies have shown that this variant leads to misfolding and accumulation of protein in hepatocyte endoplasmic reticulum." (Pan 2009 PMID:19444872, Kass 2012 PMID:22735536, Hughes 2013 PMID:25181470).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-94378609-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1989795.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 14-94378610-C-T is Pathogenic according to our data. Variant chr14-94378610-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 17967.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011169165). . 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	NM_000295.5	MANE Select	c.1096G>A	p.Glu366Lys	missense	Exon 5 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.1096G>A	p.Glu366Lys	missense	Exon 5 of 5	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.1096G>A	p.Glu366Lys	missense	Exon 7 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.1096G>A	p.Glu366Lys	missense	Exon 5 of 5	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.1096G>A	p.Glu366Lys	missense	Exon 5 of 5	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000393088.8	TSL:1	c.1096G>A	p.Glu366Lys	missense	Exon 7 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1851 AN: 152146 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0111 AC: 2797 AN: 251360 AF XY: 0.0108

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.00379

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.0162 AC: 23754 AN: 1461878 Hom.: 217 Cov.: 33 AF XY: 0.0155 AC XY: 11300 AN XY: 727242

African (AFR) AF: 0.00263 AC: 88 AN: 33480

American (AMR) AF: 0.00414 AC: 185 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00937 AC: 245 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.0187 AC: 1000 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0193 AC: 21486 AN: 1112002

Other (OTH) AF: 0.0122 AC: 735 AN: 60394

GnomAD4 genome AF: 0.0122 AC: 1851 AN: 152264 Hom.: 46 Cov.: 33 AF XY: 0.0121 AC XY: 899 AN XY: 74440

African (AFR) AF: 0.00260 AC: 108 AN: 41532

American (AMR) AF: 0.00621 AC: 95 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0174 AC: 185 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0206 AC: 1399 AN: 68014

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0149 Hom.: 45

Bravo AF: 0.0111

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0221 AC: 85

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0163 AC: 140

ExAC AF: 0.0116 AC: 1411

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0154

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
29	-	-	Alpha-1-antitrypsin deficiency (30)
11	-	-	not provided (11)
1	-	-	Chronic obstructive pulmonary disease;C0221757:Alpha-1-antitrypsin deficiency (1)
1	-	-	FRAXE (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental disorder (1)
-	1	-	not specified (1)
1	-	-	See cases (1)
1	-	-	SERPINA1-related disorder (1)
-	1	-	Susceptibility to severe coronavirus disease (COVID-19) (1)
-	-	-	Chronic obstructive pulmonary disease (1)
-	-	-	PI Z (1)
-	-	-	PI Z(AUGSBURG) (1)
-	-	-	PI Z(TUN) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.3
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.71
MPC		0.32
ClinPred		0.061	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.82
Mutation Taster		=64/36	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28929474; hg19: chr14-94844947; COSMIC: COSV99054006; COSMIC: COSV99054006;