NM_000295.5:c.*1067G>A

Variant names:

• chr14-94377382-C-T
• rs11628917
• NM_000295.5:c.*1067G>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.*1067G>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 0.101 in 152,328 control chromosomes in the GnomAD database, including 1,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1061 hom., cov: 32)
  • Exomes 𝑓: 0.12 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.225
• Publications: 12 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: Orphanet, Genomics England PanelApp, 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=-0.8).
• BP6: Variant 14-94377382-C-T is Benign according to our data. Variant chr14-94377382-C-T is described in ClinVar as Benign. ClinVar VariationId is 315007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.211 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.*1067G>A		3_prime_UTR	Exon 5 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.*1067G>A		3_prime_UTR	Exon 5 of 5	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.*1067G>A		3_prime_UTR	Exon 7 of 7	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.*1067G>A		3_prime_UTR	Exon 5 of 5	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.*1067G>A		3_prime_UTR	Exon 5 of 5	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000437397.5	TSL:1	c.*1067G>A		3_prime_UTR	Exon 6 of 6	ENSP00000408474.1	P01009-1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15377 AN: 152106 Hom.: 1055 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.115 AC: 12 AN: 104 Hom.: 0 Cov.: 0 AF XY: 0.122 AC XY: 10 AN XY: 82

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.111 AC: 10 AN: 90

Other (OTH) AF: 0.333 AC: 2 AN: 6

GnomAD4 genome AF: 0.101 AC: 15395 AN: 152224 Hom.: 1061 Cov.: 32 AF XY: 0.106 AC XY: 7864 AN XY: 74408

African (AFR) AF: 0.0404 AC: 1679 AN: 41544

American (AMR) AF: 0.217 AC: 3318 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 416 AN: 3470

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5174

South Asian (SAS) AF: 0.161 AC: 774 AN: 4812

European-Finnish (FIN) AF: 0.134 AC: 1420 AN: 10600

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7466 AN: 68006

Other (OTH) AF: 0.105 AC: 222 AN: 2114

Alfa AF: 0.102 Hom.: 403

Bravo AF: 0.101

Asia WGS AF: 0.105 AC: 367 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Alpha-1-antitrypsin deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.9
DANN	Benign	0.48
PhyloP100		-0.23
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: rs11628917; hg19: chr14-94843719; COSMIC: COSV63346192; COSMIC: COSV63346192;