rs121912713

Positions:

• chr14-94378561-A-C
• chr14-94378561-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000295.5(SERPINA1):​c.1145T>G​(p.Met382Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 0.730

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-94378561-A-C is Pathogenic according to our data. Variant chr14-94378561-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 17982.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-94378561-A-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.27427423). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.1145T>G	p.Met382Arg	missense_variant	5/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.1145T>G	p.Met382Arg	missense_variant	5/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: no assertion criteria provided

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:2

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

Hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	8.3
DANN	Benign	0.37
DEOGEN2	Benign	0.26	T;T;T;T;T;T;T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.081	N
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.1	L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;.;D;D;D
REVEL	Uncertain	0.51
Sift	Benign	0.23	T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T;.;T;T;T
Polyphen		0.019	B;B;B;B;B;B;B;B;B
Vest4		0.53
MutPred		0.72		Gain of catalytic residue at P385 (P = 2e-04);Gain of catalytic residue at P385 (P = 2e-04);Gain of catalytic residue at P385 (P = 2e-04);Gain of catalytic residue at P385 (P = 2e-04);Gain of catalytic residue at P385 (P = 2e-04);Gain of catalytic residue at P385 (P = 2e-04);Gain of catalytic residue at P385 (P = 2e-04);Gain of catalytic residue at P385 (P = 2e-04);Gain of catalytic residue at P385 (P = 2e-04);
MVP		0.70
MPC		0.061
ClinPred		0.11	T
GERP RS		-9.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.71
gMVP		0.73

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: rs121912713; hg19: chr14-94844898;