rs1802959

chr14-94378628-C-Achr14-94378628-C-Gchr14-94378628-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000295.5(SERPINA1):c.1078G>T(p.Ala360Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A360T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.25

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-94378628-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.1078G>T	p.Ala360Ser	missense_variant	5/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.1078G>T	p.Ala360Ser	missense_variant	5/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;D;D;D;D;D;D;D;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.9	M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;.;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D;D;D;D;D;.;D;D;D
Sift4G	Uncertain	0.038	D;D;D;D;D;.;D;D;D
Polyphen		0.98	D;D;D;D;D;D;D;D;D
Vest4		0.46
MutPred		0.84		Gain of catalytic residue at K359 (P = 0.0101);Gain of catalytic residue at K359 (P = 0.0101);Gain of catalytic residue at K359 (P = 0.0101);Gain of catalytic residue at K359 (P = 0.0101);Gain of catalytic residue at K359 (P = 0.0101);Gain of catalytic residue at K359 (P = 0.0101);Gain of catalytic residue at K359 (P = 0.0101);Gain of catalytic residue at K359 (P = 0.0101);Gain of catalytic residue at K359 (P = 0.0101);
MVP		1.0
MPC		0.29
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs1802959; hg19: chr14-94844965; COSMIC: COSV99054005; COSMIC: COSV99054005;