rs864622044

chr14-94380940-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000295.5(SERPINA1):c.848A>T(p.Lys283Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,894 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.82

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 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000295.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.848A>T	p.Lys283Ile	missense_variant	3/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.848A>T	p.Lys283Ile	missense_variant	3/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251484 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-1-antitrypsin deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 06, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	HerediLab, Inc.	Jul 23, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;T;T;T;T;T;T;T;.
Eigen	Benign	0.15
Eigen_PC	Benign	-0.0039
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.9	M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;.;D;D;D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;D;D;D;D
Polyphen		0.94	P;P;P;P;P;P;P;P;P;B
Vest4		0.82
MutPred		0.80		Gain of catalytic residue at E288 (P = 0.0039);Gain of catalytic residue at E288 (P = 0.0039);Gain of catalytic residue at E288 (P = 0.0039);Gain of catalytic residue at E288 (P = 0.0039);Gain of catalytic residue at E288 (P = 0.0039);Gain of catalytic residue at E288 (P = 0.0039);Gain of catalytic residue at E288 (P = 0.0039);Gain of catalytic residue at E288 (P = 0.0039);Gain of catalytic residue at E288 (P = 0.0039);Gain of catalytic residue at E288 (P = 0.0039);
MVP		0.97
MPC		0.37
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.97
gMVP		0.65

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: rs864622044; hg19: chr14-94847277;