rs1049800

Variant names:

• chr14-94380948-A-C
• rs1049800
• NM_000295.5:c.840T>G

Your query was ambiguous. Multiple possible variants found:

• chr14-94380948-A-C
• chr14-94380948-A-G
• chr14-94380948-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_000295.5(SERPINA1):​c.840T>G​(p.Asp280Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. D280V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.771
• Publications: 14 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-94380949-T-A is described in ClinVar as [Pathogenic, other]. Clinvar id is 17975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2097077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.840T>G	p.Asp280Glu	missense_variant	Exon 3 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9	c.840T>G	p.Asp280Glu	missense_variant	Exon 3 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.6
DANN	Benign	0.86
DEOGEN2	Uncertain	0.44	T;T;T;T;T;T;T;T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	.;.;.;T;.;.;.;.;.;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.2	M;M;M;M;M;M;M;M;M;M
PhyloP100		-0.77
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;.;D;D;D;D
REVEL	Benign	0.21
Sift	Benign	0.069	T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;.;T;T;T;T
Polyphen		0.046	B;B;B;B;B;B;B;B;B;B
Vest4		0.17
MutPred		0.63		Gain of catalytic residue at F276 (P = 0.0547);Gain of catalytic residue at F276 (P = 0.0547);Gain of catalytic residue at F276 (P = 0.0547);Gain of catalytic residue at F276 (P = 0.0547);Gain of catalytic residue at F276 (P = 0.0547);Gain of catalytic residue at F276 (P = 0.0547);Gain of catalytic residue at F276 (P = 0.0547);Gain of catalytic residue at F276 (P = 0.0547);Gain of catalytic residue at F276 (P = 0.0547);Gain of catalytic residue at F276 (P = 0.0547);
MVP		0.74
MPC		0.048
ClinPred		0.074	T
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.15
gMVP		0.35
Mutation Taster		=79/21	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: rs1049800; hg19: chr14-94847285;