NM_000295.5:c.*1067G>A

Variant names:

• chr14-94377382-C-T
• rs11628917
• NM_000295.5:c.*1067G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000295.5(SERPINA1):​c.*1067G>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 0.101 in 152,328 control chromosomes in the GnomAD database, including 1,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1061 hom., cov: 32)
  • Exomes 𝑓: 0.12 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.225

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-94377382-C-T is Benign according to our data. Variant chr14-94377382-C-T is described in ClinVar as [Benign]. Clinvar id is 315007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.*1067G>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	c.*1067G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15377 AN: 152106 Hom.: 1055 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.115 AC: 12 AN: 104 Hom.: 0 Cov.: 0 AF XY: 0.122 AC XY: 10 AN XY: 82

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.101 AC: 15395 AN: 152224 Hom.: 1061 Cov.: 32 AF XY: 0.106 AC XY: 7864 AN XY: 74408

Gnomad4 AFR AF: 0.0404

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.105

Alfa AF: 0.102 Hom.: 244

Bravo AF: 0.101

Asia WGS AF: 0.105 AC: 367 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	-0.80
CADD	Benign	1.9
DANN	Benign	0.48

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: rs11628917; hg19: chr14-94843719; COSMIC: COSV63346192; COSMIC: COSV63346192;