chr14-94381053-C-T

Position:

• chr14-94381053-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM2 PP3_Strong BP6_Moderate

The ENST00000393087.9(SERPINA1):​c.735G>A​(p.Met245Ile) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINA1 ENST00000393087.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.09

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• BP6: Variant 14-94381053-C-T is Benign according to our data. Variant chr14-94381053-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 219366.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.735G>A	p.Met245Ile	missense_variant	3/5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9	c.735G>A	p.Met245Ile	missense_variant	3/5	1	NM_000295.5	ENSP00000376802	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Likely benign, criteria provided, single submitter

research

HerediLab, Inc.

Aug 17, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D;D;D;D;D;D;D;D;D;.
Eigen	Benign	-0.000066
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	.;.;.;T;.;.;.;.;.;T
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.5	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	0.50	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;.;D;D;D;D
REVEL	Uncertain	0.60
Sift	Benign	0.099	T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;.;T;T;T;T
Polyphen		0.27	B;B;B;B;B;B;B;B;B;B
Vest4		0.51
MutPred		0.79		Gain of catalytic residue at V240 (P = 0);Gain of catalytic residue at V240 (P = 0);Gain of catalytic residue at V240 (P = 0);Gain of catalytic residue at V240 (P = 0);Gain of catalytic residue at V240 (P = 0);Gain of catalytic residue at V240 (P = 0);Gain of catalytic residue at V240 (P = 0);Gain of catalytic residue at V240 (P = 0);Gain of catalytic residue at V240 (P = 0);Gain of catalytic residue at V240 (P = 0);
MVP		0.91
MPC		0.18
ClinPred		0.72	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs864622053; hg19: chr14-94847390; COSMIC: COSV63345992; COSMIC: COSV63345992;