rs141620200

chr14-94379607-C-Achr14-94379607-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000295.5(SERPINA1):c.922G>T(p.Ala308Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0032 in 1,613,904 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A308T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0033 (11 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: -0.142

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059836507).
• BP6: Variant 14-94379607-C-A is Benign according to our data. Variant chr14-94379607-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 288456.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3, Benign=1}. Variant chr14-94379607-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.922G>T	p.Ala308Ser	missense_variant	4/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.922G>T	p.Ala308Ser	missense_variant	4/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 151916 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00399

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.00201 AC: 506 AN: 251208 Hom.: 1 AF XY: 0.00199 AC XY: 270 AN XY: 135784

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00331 AC: 4840 AN: 1461870 Hom.: 11 Cov.: 31 AF XY: 0.00322 AC XY: 2343 AN XY: 727240

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00176

Gnomad4 NFE exome AF: 0.00410

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00212 AC: 322 AN: 152034 Hom.: 3 Cov.: 34 AF XY: 0.00214 AC XY: 159 AN XY: 74356

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00399

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.00311 Hom.: 0

Bravo AF: 0.00173

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00234 AC: 284

EpiCase AF: 0.00273

EpiControl AF: 0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alpha-1-antitrypsin deficiency Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This 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 submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SERPINA1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2023	Identified in large case control studies in several individuals with lung disease who also harbored the Z variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes, and at least one of the individuals had normal serum concentrations of AAT (Foil et al., 2019; Ortega et al., 2020); Reported in an individual with features of alpha-1-antitrypsin deficiency who was also homozygous for the Z allele, which explained the phenotype (Bengston et al., 2016); Reported in one individual with chronic respiratory disorder in whom no second SERPINA1 variant was identified (Duk et al., 2016); In a large study evaluating the rates of venous thromboembolism (VTE), the allele frequency of this variant was found to be 0.4% higher in individuals who had experienced VTE; the variant was seen in the homozygous state in at least one individual with VTE and in the compound heterozygous state in individuals with and without VTE, but detailed clinical information, including AAT serum levels, was not provided (Manderstedt et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30223862, 25010111, 32810967, 30254761, 31661293, 26987331, 35263815) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala308Ser in exon 6 of SERPINA1: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (33/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs141620200). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2016	- -

SERPINA1-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2023

The SERPINA1 c.922G>T variant is predicted to result in the amino acid substitution p.Ala308Ser. This variant has been reported as a variant of uncertain significance in trans with the common SERPINA1 Z allele as well as the F allele in patients with chronic obstructive pulmonary disease (COPD) (Foil et al. 2018. PubMed ID: 30254761; Ortega et al. 2020. PubMed ID: 31661293). This variant is reported in 0.39% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/14-94845944-C-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Benign	0.24	T;T;T;T;T;T;T;T;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.22	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0060	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.5	M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N;N;N;N;N;.;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.065	T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;.;T;T;T;T
Polyphen		0.0030	B;B;B;B;B;B;B;B;B;B
Vest4		0.44
MVP		0.99
MPC		0.059
ClinPred		0.014	T
GERP RS		3.4
Varity_R		0.47
gMVP		0.46

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: rs141620200; hg19: chr14-94845944;