chr14-94388515-C-T

Variant names:

• chr14-94388515-C-T
• rs6575424
• NM_000295.5:c.-5+45G>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+45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 151,912 control chromosomes in the GnomAD database, including 12,088 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 0.38 (12088 hom., cov: 31)
  • Exomes 𝑓: 0.28 (24 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPINA1 NM_000295.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770
• Publications: 13 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, PanelApp Australia, 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000295.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	NM_000295.5	MANE Select	c.-5+45G>A		intron	N/A	NP_000286.3
	SERPINA1	NM_001002235.3		c.-5+1942G>A		intron	N/A	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.-5+45G>A		intron	N/A	NP_001002236.1	E9KL23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.-5+45G>A		intron	N/A	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.-5+1905G>A		intron	N/A	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000393088.8	TSL:1	c.-5+45G>A		intron	N/A	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58319 AN: 151794 Hom.: 12084 Cov.: 31

Gnomad AFR AF: 0.550

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.383

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.275 AC: 126 AN: 458 Hom.: 24 Cov.: 0 AF XY: 0.261 AC XY: 91 AN XY: 348

African (AFR) AF: 0.750 AC: 6 AN: 8

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.333 AC: 6 AN: 18

South Asian (SAS) AF: 0.333 AC: 2 AN: 6

European-Finnish (FIN) AF: 0.500 AC: 5 AN: 10

Middle Eastern (MID) AF: 0.333 AC: 2 AN: 6

European-Non Finnish (NFE) AF: 0.254 AC: 101 AN: 398

Other (OTH) AF: 0.400 AC: 4 AN: 10

GnomAD4 genome AF: 0.384 AC: 58357 AN: 151912 Hom.: 12088 Cov.: 31 AF XY: 0.376 AC XY: 27944 AN XY: 74248

African (AFR) AF: 0.549 AC: 22717 AN: 41378

American (AMR) AF: 0.274 AC: 4190 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1131 AN: 3466

East Asian (EAS) AF: 0.307 AC: 1578 AN: 5148

South Asian (SAS) AF: 0.392 AC: 1886 AN: 4816

European-Finnish (FIN) AF: 0.260 AC: 2748 AN: 10588

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22960 AN: 67936

Other (OTH) AF: 0.388 AC: 817 AN: 2106

Alfa AF: 0.343 Hom.: 14787

Bravo AF: 0.390

Asia WGS AF: 0.324 AC: 1130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.1
DANN	Benign	0.42
PhyloP100		0.077
PromoterAI		-0.018	Neutral
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: rs6575424; hg19: chr14-94854852;