14-94384993-A-G

Variant names:

• chr14-94384993-A-G
• rs2753934
• NM_000295.5:c.-4-1752T>C

Variant summary

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

The NM_000295.5(SERPINA1):​c.-4-1752T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.851 in 152,280 control chromosomes in the GnomAD database, including 55,421 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 0.85 (55421 hom., cov: 34)
• Consequence: SERPINA1 NM_000295.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0790
• Publications: 8 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.-4-1752T>C		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.-4-1752T>C		intron_variant	Intron 1 of 4	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes AF: 0.851 AC: 129452 AN: 152162 Hom.: 55363 Cov.: 34

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.879

Gnomad ASJ AF: 0.845

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.869

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.886

Gnomad NFE AF: 0.794

Gnomad OTH AF: 0.867

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

GnomAD4 genome AF: 0.851 AC: 129569 AN: 152280 Hom.: 55421 Cov.: 34 AF XY: 0.854 AC XY: 63562 AN XY: 74452

African (AFR) AF: 0.940 AC: 39052 AN: 41566

American (AMR) AF: 0.879 AC: 13456 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 2933 AN: 3470

East Asian (EAS) AF: 0.902 AC: 4675 AN: 5184

South Asian (SAS) AF: 0.869 AC: 4189 AN: 4822

European-Finnish (FIN) AF: 0.798 AC: 8464 AN: 10606

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.794 AC: 53977 AN: 68010

Other (OTH) AF: 0.866 AC: 1831 AN: 2114

Alfa AF: 0.815 Hom.: 86668

Bravo AF: 0.862

Asia WGS AF: 0.868 AC: 3019 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.4
DANN	Benign	0.59
PhyloP100		0.079
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs2753934; hg19: chr14-94851330;