14-94381043-C-T

Variant names:

• chr14-94381043-C-T
• rs764220898
• NM_000295.5:c.745G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM5 PP3

The NM_000295.5(SERPINA1):​c.745G>A​(p.Gly249Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G249R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.723
• Publications: 18 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: Uncertain_significance. The variant received 3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-94381043-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 189018.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

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.745G>A	p.Gly249Ser	missense	Exon 3 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.745G>A	p.Gly249Ser	missense	Exon 3 of 5	NP_001002235.1
	SERPINA1	NM_001002236.3		c.745G>A	p.Gly249Ser	missense	Exon 5 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.745G>A	p.Gly249Ser	missense	Exon 3 of 5	ENSP00000376802.4
	SERPINA1	ENST00000355814.8	TSL:1	c.745G>A	p.Gly249Ser	missense	Exon 3 of 5	ENSP00000348068.4
	SERPINA1	ENST00000393088.8	TSL:1	c.745G>A	p.Gly249Ser	missense	Exon 5 of 7	ENSP00000376803.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251410 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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

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: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.72
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.45
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Polyphen		0.83	P
Vest4		0.17
MutPred		0.68		Gain of catalytic residue at N252 (P = 0.0179)
MVP		0.99
MPC		0.28
ClinPred		0.94	D
GERP RS		4.2
Varity_R		0.84
gMVP		0.56
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs764220898; hg19: chr14-94847380;