14-94383052-G-T

Variant names:

• chr14-94383052-G-T
• rs762321137
• NM_000295.5:c.186C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000295.5(SERPINA1):​c.186C>A​(p.Tyr62*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 stop_gained
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.26
• Publications: 1 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-94383052-G-T is Pathogenic according to our data. Variant chr14-94383052-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 371266.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	NM_000295.5	MANE Select	c.186C>A	p.Tyr62*	stop_gained	Exon 2 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.186C>A	p.Tyr62*	stop_gained	Exon 2 of 5	NP_001002235.1
	SERPINA1	NM_001002236.3		c.186C>A	p.Tyr62*	stop_gained	Exon 4 of 7	NP_001002236.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.186C>A	p.Tyr62*	stop_gained	Exon 2 of 5	ENSP00000376802.4
	SERPINA1	ENST00000355814.8	TSL:1	c.186C>A	p.Tyr62*	stop_gained	Exon 2 of 5	ENSP00000348068.4
	SERPINA1	ENST00000393088.8	TSL:1	c.186C>A	p.Tyr62*	stop_gained	Exon 4 of 7	ENSP00000376803.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251338 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461532 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111688

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.000156 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:1

Aug 09, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		3.3
Vest4		0.83
GERP RS		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs762321137; hg19: chr14-94849389;