rs8004738

Variant names:

• chr14-94390577-G-A
• rs8004738
• ENST00000355814.8:c.-162C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-94390577-G-A
• chr14-94390577-G-C
• chr14-94390577-G-T

Variant summary

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

The ENST00000355814.8(SERPINA1):​c.-162C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 152,556 control chromosomes in the GnomAD database, including 23,234 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 0.54 (23168 hom., cov: 33)
  • Exomes 𝑓: 0.56 (66 hom.)
• Consequence: SERPINA1 ENST00000355814.8 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 26 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

ENSG00000256357 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_001002235.3	c.-125C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5		NP_001002235.1
SERPINA1	NM_001002236.3	c.-439C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7		NP_001002236.1
SERPINA1	NM_001127700.2	c.-162C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5		NP_001121172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000355814.8	c.-162C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 5	1		ENSP00000348068.4
SERPINA1	ENST00000393088.8	c.-439C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 7	1		ENSP00000376803.4
SERPINA1	ENST00000404814.8	c.-226C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	1		ENSP00000385960.4

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82488 AN: 151992 Hom.: 23132 Cov.: 33

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.531

GnomAD4 exome AF: 0.561 AC: 250 AN: 446 Hom.: 66 Cov.: 0 AF XY: 0.558 AC XY: 203 AN XY: 364

African (AFR) AF: 0.333 AC: 2 AN: 6

American (AMR) AF: 0.500 AC: 4 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 4 AN: 6

East Asian (EAS) AF: 0.571 AC: 8 AN: 14

South Asian (SAS) AF: 0.625 AC: 5 AN: 8

European-Finnish (FIN) AF: 1.00 AC: 4 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.551 AC: 206 AN: 374

Other (OTH) AF: 0.708 AC: 17 AN: 24

GnomAD4 genome AF: 0.543 AC: 82582 AN: 152110 Hom.: 23168 Cov.: 33 AF XY: 0.540 AC XY: 40184 AN XY: 74358

African (AFR) AF: 0.671 AC: 27858 AN: 41512

American (AMR) AF: 0.373 AC: 5704 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1917 AN: 3472

East Asian (EAS) AF: 0.598 AC: 3075 AN: 5138

South Asian (SAS) AF: 0.600 AC: 2898 AN: 4830

European-Finnish (FIN) AF: 0.505 AC: 5338 AN: 10572

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.501 AC: 34084 AN: 67982

Other (OTH) AF: 0.535 AC: 1130 AN: 2114

Alfa AF: 0.501 Hom.: 7520

Bravo AF: 0.533

Asia WGS AF: 0.570 AC: 1981 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.6
DANN	Benign	0.86
PhyloP100		-1.1
PromoterAI		-0.014	Neutral
Mutation Taster		=300/0	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: rs8004738; hg19: chr14-94856914; COSMIC: COSV63345504; COSMIC: COSV63345504;