rs11832

Variant names:

• chr14-94377228-T-C
• rs11832
• NM_000295.5:c.*1221A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-94377228-T-C
• chr14-94377228-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000295.5(SERPINA1):​c.*1221A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 152,176 control chromosomes in the GnomAD database, including 32,278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (32275 hom., cov: 33)
  • Exomes 𝑓: 0.41 (3 hom.)
• Consequence: SERPINA1 NM_000295.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.65
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-94377228-T-C is Benign according to our data. Variant chr14-94377228-T-C is described in ClinVar as Benign. ClinVar VariationId is 315004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.*1221A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9	c.*1221A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94899 AN: 152026 Hom.: 32210 Cov.: 33

Gnomad AFR AF: 0.899

Gnomad AMI AF: 0.553

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.651

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.626

GnomAD4 exome AF: 0.406 AC: 13 AN: 32 Hom.: 3 Cov.: 0 AF XY: 0.409 AC XY: 9 AN XY: 22

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 2 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.417 AC: 10 AN: 24

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.625 AC: 95028 AN: 152144 Hom.: 32275 Cov.: 33 AF XY: 0.624 AC XY: 46406 AN XY: 74380

African (AFR) AF: 0.900 AC: 37383 AN: 41554

American (AMR) AF: 0.561 AC: 8575 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.651 AC: 2259 AN: 3468

East Asian (EAS) AF: 0.369 AC: 1909 AN: 5172

South Asian (SAS) AF: 0.758 AC: 3662 AN: 4830

European-Finnish (FIN) AF: 0.480 AC: 5079 AN: 10574

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.502 AC: 34123 AN: 67950

Other (OTH) AF: 0.629 AC: 1328 AN: 2110

Alfa AF: 0.549 Hom.: 14099

Bravo AF: 0.632

Asia WGS AF: 0.576 AC: 2005 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-1-antitrypsin deficiency Benign:1

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:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.91
DANN	Benign	0.67
PhyloP100		-1.6
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: rs11832; hg19: chr14-94843565;