rs1243166

Variant names:

• chr14-94377481-A-G
• rs1243166
• NM_000295.5:c.*968T>C

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.*968T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 152,272 control chromosomes in the GnomAD database, including 37,393 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37350 hom., cov: 32)
  • Exomes 𝑓: 0.64 (43 hom.)
• Consequence: SERPINA1 NM_000295.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.426

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=-0.83).
• BP6: Variant 14-94377481-A-G is Benign according to our data. Variant chr14-94377481-A-G is described in ClinVar as [Benign]. Clinvar id is 315008.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.*968T>C		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.*968T>C		3_prime_UTR_variant	Exon 5 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106082 AN: 151956 Hom.: 37301 Cov.: 32

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.702

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.697

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.712

GnomAD4 exome AF: 0.641 AC: 127 AN: 198 Hom.: 43 Cov.: 0 AF XY: 0.639 AC XY: 92 AN XY: 144

Gnomad4 AFR exome AF: 1.00

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.714

Gnomad4 NFE exome AF: 0.597

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.698 AC: 106180 AN: 152074 Hom.: 37350 Cov.: 32 AF XY: 0.703 AC XY: 52240 AN XY: 74316

Gnomad4 AFR AF: 0.770

Gnomad4 AMR AF: 0.755

Gnomad4 ASJ AF: 0.697

Gnomad4 EAS AF: 0.650

Gnomad4 SAS AF: 0.658

Gnomad4 FIN AF: 0.714

Gnomad4 NFE AF: 0.645

Gnomad4 OTH AF: 0.704

Alfa AF: 0.659 Hom.: 43994

Bravo AF: 0.707

Asia WGS AF: 0.667 AC: 2319 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 12, 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	-0.83
CADD	Benign	2.7
DANN	Benign	0.76

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: rs1243166; hg19: chr14-94843818;