14-94387927-C-T

Variant names:

• chr14-94387927-C-T
• rs3748312
• NM_000295.5:c.-5+633G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000295.5(SERPINA1):​c.-5+633G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 151,972 control chromosomes in the GnomAD database, including 6,167 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (6167 hom., cov: 31)
• Consequence: SERPINA1 NM_000295.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.280
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.-5+633G>A		intron_variant	Intron 1 of 4	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9	c.-5+633G>A		intron_variant	Intron 1 of 4	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36239 AN: 151854 Hom.: 6163 Cov.: 31

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.228

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.239 AC: 36272 AN: 151972 Hom.: 6167 Cov.: 31 AF XY: 0.234 AC XY: 17382 AN XY: 74264

African (AFR) AF: 0.481 AC: 19918 AN: 41380

American (AMR) AF: 0.131 AC: 2006 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3466

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5176

South Asian (SAS) AF: 0.143 AC: 689 AN: 4816

European-Finnish (FIN) AF: 0.171 AC: 1813 AN: 10576

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10332 AN: 67966

Other (OTH) AF: 0.226 AC: 476 AN: 2110

Alfa AF: 0.133 Hom.: 671

Bravo AF: 0.245

Asia WGS AF: 0.0880 AC: 307 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.91
PhyloP100		-0.28
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: rs3748312; hg19: chr14-94854264;