14-94381043-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-94381043-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.745G>A	p.Gly249Ser	missense_variant	3/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.745G>A	p.Gly249Ser	missense_variant	3/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251410 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135872

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T;T;T;T;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.57	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.6	L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;.;D;D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.17	T;T;T;T;T;.;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T;.;T;T;T;T
Polyphen		0.83	P;P;P;P;P;P;P;P;P;P
Vest4		0.17
MutPred		0.68		Gain of catalytic residue at N252 (P = 0.0179);Gain of catalytic residue at N252 (P = 0.0179);Gain of catalytic residue at N252 (P = 0.0179);Gain of catalytic residue at N252 (P = 0.0179);Gain of catalytic residue at N252 (P = 0.0179);Gain of catalytic residue at N252 (P = 0.0179);Gain of catalytic residue at N252 (P = 0.0179);Gain of catalytic residue at N252 (P = 0.0179);Gain of catalytic residue at N252 (P = 0.0179);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs764220898; hg19: chr14-94847380;