rs28931568

chr14-94382966-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000295.5(SERPINA1):c.272G>A(p.Gly91Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic,other (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Pathogenic; other no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 5.71

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 14-94382966-C-T is Pathogenic according to our data. Variant chr14-94382966-C-T is described in ClinVar as [Pathogenic, other]. Clinvar id is 17966.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-94382966-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.272G>A	p.Gly91Glu	missense_variant	2/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.272G>A	p.Gly91Glu	missense_variant	2/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	curation	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	Reduced enzyme activity -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	May 01, 2014	- -

PI M(MINERAL SPRINGS) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;D;D;D;D;D;D;D;.;.;.;D;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;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;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.9	D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.;D;D;D;D;.;.;.;D;.
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.;.;.;.;.
Vest4		0.91
MutPred		0.87		Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);.;Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);Gain of catalytic residue at A86 (P = 0.001);
MVP		1.0
MPC		0.34
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.98
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28931568; hg19: chr14-94849303;