14-94381134-C-A

Variant names:

• chr14-94381134-C-A
• rs1445192595
• NM_000295.5:c.654G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM2 PP3_Strong BP6_Moderate

The NM_000295.5(SERPINA1):​c.654G>T​(p.Trp218Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,010 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 benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.95
• Publications: 3 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, 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• BP6: Variant 14-94381134-C-A is Benign according to our data. Variant chr14-94381134-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 626302.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.654G>T	p.Trp218Cys	missense_variant	Exon 3 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9	c.654G>T	p.Trp218Cys	missense_variant	Exon 3 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460010 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726272

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alpha-1-antitrypsin deficiency Benign:1

Oct 24, 2013

HerediLab, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;.;.;D;.;.;.;.;.;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H;H;H;H;H;H
PhyloP100		7.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-12	D;D;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.038	D;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D;.;D;D;D;D
Polyphen		0.96	D;D;D;D;D;D;D;D;D;D
Vest4		0.80
MutPred		0.82		Gain of catalytic residue at K215 (P = 0.0047);Gain of catalytic residue at K215 (P = 0.0047);Gain of catalytic residue at K215 (P = 0.0047);Gain of catalytic residue at K215 (P = 0.0047);Gain of catalytic residue at K215 (P = 0.0047);Gain of catalytic residue at K215 (P = 0.0047);Gain of catalytic residue at K215 (P = 0.0047);Gain of catalytic residue at K215 (P = 0.0047);Gain of catalytic residue at K215 (P = 0.0047);Gain of catalytic residue at K215 (P = 0.0047);
MVP		0.97
MPC		0.37
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.89
Mutation Taster		=13/87	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: rs1445192595; hg19: chr14-94847471;