rs20546

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. L142L) has been classified as Likely 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:10
• Conservation: PhyloP100: 1.00
• Publications: 15 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, PanelApp Australia, 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 -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 VariationId is 178806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000295.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	NM_000295.5	MANE Select	c.424C>T	p.Leu142Leu	synonymous	Exon 2 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.424C>T	p.Leu142Leu	synonymous	Exon 2 of 5	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.424C>T	p.Leu142Leu	synonymous	Exon 4 of 7	NP_001002236.1	E9KL23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.424C>T	p.Leu142Leu	synonymous	Exon 2 of 5	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.424C>T	p.Leu142Leu	synonymous	Exon 2 of 5	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000393088.8	TSL:1	c.424C>T	p.Leu142Leu	synonymous	Exon 4 of 7	ENSP00000376803.4	P01009-1

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

GnomAD2 exomes AF: 0.0392 AC: 9846 AN: 251398 AF XY: 0.0332

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 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

African (AFR) AF: 0.00612 AC: 205 AN: 33480

American (AMR) AF: 0.184 AC: 8226 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 536 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00605 AC: 522 AN: 86258

European-Finnish (FIN) AF: 0.0162 AC: 863 AN: 53418

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.0238 AC: 26500 AN: 1112010

Other (OTH) AF: 0.0226 AC: 1363 AN: 60396

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

African (AFR) AF: 0.00707 AC: 294 AN: 41578

American (AMR) AF: 0.162 AC: 2477 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4828

European-Finnish (FIN) AF: 0.0148 AC: 157 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0230 AC: 1565 AN: 68028

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0264 Hom.: 283

Bravo AF: 0.0395

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Alpha-1-antitrypsin deficiency (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.8
DANN	Benign	0.39
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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