rs28931572

Variant names:

• chr14-94382891-A-T
• rs28931572
• NM_000295.5:c.347T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000295.5(SERPINA1):​c.347T>A​(p.Ile116Asn) 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. Variant has been reported in ClinVar as Pathogenic,other (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Pathogenic; other no assertion criteria provided P:2 O:2
• Conservation: PhyloP100: 3.67

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 14-94382891-A-T is Pathogenic according to our data. Variant chr14-94382891-A-T is described in ClinVar as [Pathogenic, other]. Clinvar id is 17987.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-94382891-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.347T>A	p.Ile116Asn	missense_variant	Exon 2 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9	c.347T>A	p.Ile116Asn	missense_variant	Exon 2 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic; other

Submissions summary: Pathogenic:2 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Alpha-1-antitrypsin deficiency Pathogenic:2

May 01, 2014

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 08, 2014

Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

Reduced enzyme activity -

PI NULL(LUDWIGSHAFEN) Other:1

Jul 20, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

PI Q0(LUDWIGSHAFEN) Other:1

Jul 20, 2016

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T;T;T;T;T;T;T;T;.;.;.;T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.80	.;.;.;T;.;.;.;.;.;T;D;.;.;.
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;H;H;H;H;H;H;.;.;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-6.7	D;D;D;D;D;.;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;D;D;D;D;.;.;.;D
Polyphen		1.0	D;D;D;D;D;D;D;D;D;D;.;.;.;.
Vest4		0.84
MutPred		0.83		Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);.;Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);Gain of disorder (P = 0.0102);
MVP		1.0
MPC		0.37
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.90

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: rs28931572; hg19: chr14-94849228;