rs141620200

Variant names:

• chr14-94379607-C-A
• rs141620200
• NM_000295.5:c.922G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-94379607-C-A
• chr14-94379607-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 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. 16/22 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
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• alpha 1-antitrypsin deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 288456.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00212 (322/152034) while in subpopulation NFE AF = 0.00399 (271/67956). AF 95% confidence interval is 0.0036. There are 3 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.922G>T	p.Ala308Ser	missense_variant	Exon 4 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9	c.922G>T	p.Ala308Ser	missense_variant	Exon 4 of 5	1	NM_000295.5	ENSP00000376802.4

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

GnomAD2 exomes AF: 0.00201 AC: 506 AN: 251208 AF XY: 0.00199

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 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

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 21 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00176 AC: 94 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00410 AC: 4558 AN: 1112008

Other (OTH) AF: 0.00242 AC: 146 AN: 60394

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

African (AFR) AF: 0.000723 AC: 30 AN: 41484

American (AMR) AF: 0.000197 AC: 3 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00399 AC: 271 AN: 67956

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00288 Hom.: 6

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Uncertain:1 Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SERPINA1: BS2

Aug 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual with features of alpha-1-antitrypsin deficiency who was also homozygous for the Z allele, which explained the phenotype (Per Bengtson et al. Phenotyping of a-1-Antitrypsin by liquid chromatographyhigh resolution mass spectrometry. Clinical Mass Spectrometry. 2016); 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 (PMID: 31661293, 30254761); Reported in one individual with chronic respiratory disorder in whom no second SERPINA1 variant was identified (PMID: 26987331); 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 (PMID: 35263815); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30223862, 25010111, 32810967, 30254761, 35263815, 26987331, 31661293, 38637533, 36367950)

not specified Benign:2

Jun 02, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

SERPINA1-related disorder Uncertain:1

Mar 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. 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
LIST_S2	Benign	0.0	.;.;.;T;.;.;.;.;.;T
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
PhyloP100		-0.14
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
Vest4		0.44
ClinPred		0.014	T
GERP RS		3.4
Varity_R		0.47
gMVP		0.46
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs141620200; hg19: chr14-94845944;