14-94378547-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000295.5(SERPINA1):​c.1159G>A​(p.Glu387Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,770 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

SERPINA1
NM_000295.5 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4O:1

Conservation

PhyloP100: -6.16
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.012122005).
BP6
Variant 14-94378547-C-T is Benign according to our data. Variant chr14-94378547-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17964.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr14-94378547-C-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SERPINA1NM_000295.5 linkc.1159G>A p.Glu387Lys missense_variant 5/5 ENST00000393087.9 NP_000286.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SERPINA1ENST00000393087.9 linkc.1159G>A p.Glu387Lys missense_variant 5/51 NM_000295.5 ENSP00000376802.4 P01009-1

Frequencies

GnomAD3 genomes
AF:
0.000415
AC:
63
AN:
151844
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00328
Gnomad SAS
AF:
0.00125
Gnomad FIN
AF:
0.00303
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000386
AC:
97
AN:
251306
Hom.:
0
AF XY:
0.000456
AC XY:
62
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00141
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00263
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000127
AC:
186
AN:
1461808
Hom.:
1
Cov.:
33
AF XY:
0.000151
AC XY:
110
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000630
Gnomad4 SAS exome
AF:
0.000348
Gnomad4 FIN exome
AF:
0.00165
Gnomad4 NFE exome
AF:
0.0000162
Gnomad4 OTH exome
AF:
0.000397
GnomAD4 genome
AF:
0.000408
AC:
62
AN:
151962
Hom.:
0
Cov.:
33
AF XY:
0.000633
AC XY:
47
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00309
Gnomad4 SAS
AF:
0.00125
Gnomad4 FIN
AF:
0.00303
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000875
Hom.:
0
Bravo
AF:
0.000125
ExAC
AF:
0.000288
AC:
35
Asia WGS
AF:
0.00606
AC:
21
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Alpha-1-antitrypsin deficiency Uncertain:1Benign:3
Benign, no assertion criteria providedcurationDepartment of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley HospitalDec 08, 2014- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Benign, no assertion criteria providedliterature onlyGeneReviewsMay 01, 2014- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 19, 2017- -
SERPINA1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 30, 2021This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
PI CHRISTCHURCH Other:1
other, no assertion criteria providedliterature onlyOMIMJul 15, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
0.018
DANN
Benign
0.30
DEOGEN2
Benign
0.18
T;T;T;T;T;T;T;T;T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.018
N
LIST_S2
Benign
0.64
.;.;.;T;.;.;.;.;.
M_CAP
Benign
0.044
D
MetaRNN
Benign
0.012
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Benign
1.3
L;L;L;L;L;L;L;L;L
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.65
N;N;N;N;N;.;N;N;N
REVEL
Benign
0.28
Sift
Benign
0.83
T;T;T;T;T;.;T;T;T
Sift4G
Benign
0.92
T;T;T;T;T;.;T;T;T
Polyphen
0.11
B;B;B;B;B;B;B;B;B
Vest4
0.16
MVP
0.82
MPC
0.075
ClinPred
0.022
T
GERP RS
-9.6
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
3.2
Varity_R
0.37
gMVP
0.38

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121912712; hg19: chr14-94844884; COSMIC: COSV63346397; COSMIC: COSV63346397; API