rs753313462

Variant names:

• chr14-94382902-C-T
• rs753313462
• NM_000295.5:c.336G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000295.5(SERPINA1):​c.336G>A​(p.Pro112Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -4.72
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-94382902-C-T is Benign according to our data. Variant chr14-94382902-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458845.
• BP7: Synonymous conserved (PhyloP=-4.72 with no splicing effect.

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.336G>A	p.Pro112Pro	synonymous	Exon 2 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.336G>A	p.Pro112Pro	synonymous	Exon 2 of 5	NP_001002235.1
	SERPINA1	NM_001002236.3		c.336G>A	p.Pro112Pro	synonymous	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.336G>A	p.Pro112Pro	synonymous	Exon 2 of 5	ENSP00000376802.4
	SERPINA1	ENST00000355814.8	TSL:1	c.336G>A	p.Pro112Pro	synonymous	Exon 2 of 5	ENSP00000348068.4
	SERPINA1	ENST00000393088.8	TSL:1	c.336G>A	p.Pro112Pro	synonymous	Exon 4 of 7	ENSP00000376803.4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251308 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000541 AC: 79 AN: 1461154 Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 36 AN XY: 726738

African (AFR) AF: 0.0000299 AC: 1 AN: 33434

American (AMR) AF: 0.000179 AC: 8 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1111432

Other (OTH) AF: 0.0000663 AC: 4 AN: 60364

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74364

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68050

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000264

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-0.77
CADD	Benign	0.091
DANN	Benign	0.42
PhyloP100		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs753313462; hg19: chr14-94849239; COSMIC: COSV108876120; COSMIC: COSV108876120;