rs20546

Variant names:

• chr14-94382814-G-A
• rs20546
• NM_000295.5:c.424C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000295.5(SERPINA1):​c.424C>T​(p.Leu142Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,614,230 control chromosomes in the GnomAD database, including 1,537 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (279 hom., cov: 33)
  • Exomes 𝑓: 0.026 (1258 hom.)
• Consequence: SERPINA1 NM_000295.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.00

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 14-94382814-G-A is Benign according to our data. Variant chr14-94382814-G-A is described in ClinVar as [Benign]. Clinvar id is 178806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-94382814-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.424C>T	p.Leu142Leu	synonymous_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	c.424C>T	p.Leu142Leu	synonymous_variant	Exon 2 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4671 AN: 152226 Hom.: 274 Cov.: 33

Gnomad AFR AF: 0.00709

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0392 AC: 9846 AN: 251398 Hom.: 718 AF XY: 0.0332 AC XY: 4512 AN XY: 135868

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00565

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0262 AC: 38237 AN: 1461886 Hom.: 1258 Cov.: 31 AF XY: 0.0247 AC XY: 17994 AN XY: 727244

Gnomad4 AFR exome AF: 0.00612

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.0205

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00605

Gnomad4 FIN exome AF: 0.0162

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0226

GnomAD4 genome AF: 0.0308 AC: 4687 AN: 152344 Hom.: 279 Cov.: 33 AF XY: 0.0334 AC XY: 2486 AN XY: 74494

Gnomad4 AFR AF: 0.00707

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0230

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0254 Hom.: 180

Bravo AF: 0.0395

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leu142Leu in exon 4 of SERPINA1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 2.4% (204/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs20546). -

Apr 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Alpha-1-antitrypsin deficiency Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 08, 2014

Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Nov 28, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.8
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs20546; hg19: chr14-94849151; COSMIC: COSV63345711; COSMIC: COSV63345711;