14-94377118-C-T

Variant names:

• chr14-94377118-C-T
• rs11568814
• NM_000295.5:c.*1331G>A

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.*1331G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0844 in 152,256 control chromosomes in the GnomAD database, including 678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (678 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPINA1 NM_000295.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.11
• Publications: 4 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=-0.83).
• BP6: Variant 14-94377118-C-T is Benign according to our data. Variant chr14-94377118-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 314999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.*1331G>A		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.*1331G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes AF: 0.0843 AC: 12828 AN: 152138 Hom.: 673 Cov.: 33

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0848

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.0764

Gnomad OTH AF: 0.109

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0844 AC: 12844 AN: 152256 Hom.: 678 Cov.: 33 AF XY: 0.0831 AC XY: 6185 AN XY: 74464

African (AFR) AF: 0.114 AC: 4738 AN: 41530

American (AMR) AF: 0.0613 AC: 937 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 602 AN: 3470

East Asian (EAS) AF: 0.00520 AC: 27 AN: 5192

South Asian (SAS) AF: 0.0836 AC: 403 AN: 4818

European-Finnish (FIN) AF: 0.0490 AC: 520 AN: 10612

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.0764 AC: 5199 AN: 68028

Other (OTH) AF: 0.108 AC: 228 AN: 2112

Alfa AF: 0.0531 Hom.: 69

Bravo AF: 0.0868

Asia WGS AF: 0.0450 AC: 156 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alpha-1-antitrypsin deficiency Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

PI KALSHEKER-POLLER Other:1

Jul 20, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.46
DANN	Benign	0.66
PhyloP100		-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: rs11568814; hg19: chr14-94843455;