14-94377118-C-T

Variant names:

• chr14-94377118-C-T
• rs11568814
• NM_000295.5:c.*1331G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000295.5(SERPINA1):​c.*1331G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0844 in 152,256 control chromosomes in the GnomAD database, including 678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (678 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SERPINA1 NM_000295.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -1.11
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-94377118-C-T is Benign according to our data. Variant chr14-94377118-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 314999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 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.*1331G>A		3_prime_UTR	Exon 5 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.*1331G>A		3_prime_UTR	Exon 5 of 5	NP_001002235.1
	SERPINA1	NM_001002236.3		c.*1331G>A		3_prime_UTR	Exon 7 of 7	NP_001002236.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.*1331G>A		3_prime_UTR	Exon 5 of 5	ENSP00000376802.4
	SERPINA1	ENST00000355814.8	TSL:1	c.*1331G>A		3_prime_UTR	Exon 5 of 5	ENSP00000348068.4
	SERPINA1	ENST00000437397.5	TSL:1	c.*1331G>A		3_prime_UTR	Exon 6 of 6	ENSP00000408474.1

Frequencies

GnomAD3 genomes AF: 0.0843 AC: 12828 AN: 152138 Hom.: 673 Cov.: 33

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0614

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.0848

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.0764

Gnomad OTH AF: 0.109

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0844 AC: 12844 AN: 152256 Hom.: 678 Cov.: 33 AF XY: 0.0831 AC XY: 6185 AN XY: 74464

African (AFR) AF: 0.114 AC: 4738 AN: 41530

American (AMR) AF: 0.0613 AC: 937 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 602 AN: 3470

East Asian (EAS) AF: 0.00520 AC: 27 AN: 5192

South Asian (SAS) AF: 0.0836 AC: 403 AN: 4818

European-Finnish (FIN) AF: 0.0490 AC: 520 AN: 10612

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.0764 AC: 5199 AN: 68028

Other (OTH) AF: 0.108 AC: 228 AN: 2112

Alfa AF: 0.0531 Hom.: 69

Bravo AF: 0.0868

Asia WGS AF: 0.0450 AC: 156 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Alpha-1-antitrypsin deficiency (2)
-	-	1	not provided (1)
-	-	-	PI KALSHEKER-POLLER (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.46
DANN	Benign	0.66
PhyloP100		-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: rs11568814; hg19: chr14-94843455;