14-94378528-G-C

Variant names:

• chr14-94378528-G-C
• rs199422209
• NM_000295.5:c.1178C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM5 PP3_Strong PP5_Very_Strong

The NM_000295.5(SERPINA1):​c.1178C>G​(p.Pro393Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000274 in 1,461,884 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P393T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.93
• Publications: 23 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: Pathogenic. The variant received 14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-94378529-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219360.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 14-94378528-G-C is Pathogenic according to our data. Variant chr14-94378528-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1066793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1178C>G	p.Pro393Arg	missense	Exon 5 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.1178C>G	p.Pro393Arg	missense	Exon 5 of 5	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.1178C>G	p.Pro393Arg	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.1178C>G	p.Pro393Arg	missense	Exon 5 of 5	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.1178C>G	p.Pro393Arg	missense	Exon 5 of 5	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000393088.8	TSL:1	c.1178C>G	p.Pro393Arg	missense	Exon 7 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251476 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1112006

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Alpha-1-antitrypsin deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		6.9
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.86		Gain of MoRF binding (P = 0.0176)
MVP		1.0
MPC		0.32
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.70
gMVP		0.79
Mutation Taster		=5/95	disease causing

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: rs199422209; hg19: chr14-94844865;