Genetic Variant NM_000295.5:c.415G>T (chr14-94382823-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000295.5(SERPINA1):c.415G>T(p.Gly139Cys) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G139S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

SERPINA1
NM_000295.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.59

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-94382823-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5 link	c.415G>T	p.Gly139Cys	missense_variant	Exon 2 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9 link	c.415G>T	p.Gly139Cys	missense_variant	Exon 2 of 5	1	NM_000295.5	ENSP00000376802.4		P01009-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.415G>T (p.G139C) alteration is located in exon 2 (coding exon 1) of the SERPINA1 gene. This alteration results from a G to T substitution at nucleotide position 415, causing the glycine (G) at amino acid position 139 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;D;D;D;D;D;D;D;D;.;.;.;T

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

.;.;.;T;.;.;.;.;.;T;T;.;.

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.2

H;H;H;H;H;H;H;H;H;H;.;.;.

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-7.4

D;D;D;D;D;.;D;D;D;D;D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;D;D;D;D;.;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;.;D;D;D;D;.;.;.

Polyphen

1.0

D;D;D;D;D;D;D;D;D;D;.;.;.

Vest4

0.75

MutPred

0.81

Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);.;Gain of catalytic residue at N140 (P = 0.0011);Gain of catalytic residue at N140 (P = 0.0011);

MVP

1.0

MPC

0.32

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.95

gMVP

0.84

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over