14-94383161-T-G

Position:

• chr14-94383161-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000295.5(SERPINA1):​c.77A>C​(p.Asp26Ala) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Benign; other no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: -0.227

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1347833).
• BP6: Variant 14-94383161-T-G is Benign according to our data. Variant chr14-94383161-T-G is described in ClinVar as [Benign, other]. Clinvar id is 17983.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-94383161-T-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.77A>C	p.Asp26Ala	missense_variant	2/5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9	c.77A>C	p.Asp26Ala	missense_variant	2/5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign; other

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Alpha-1-antitrypsin deficiency Benign:1

Benign, no assertion criteria provided

curation

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

Dec 08, 2014

- -

PI V(MUNICH) Other:1

other, no assertion criteria provided

literature only

OMIM

Jul 15, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	0.00092	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	9.4
DANN	Benign	0.89
DEOGEN2	Benign	0.35	T;T;T;T;T;T;T;T;T;.;.;T;T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.60	.;.;.;T;.;.;.;.;.;T;.;.;.;.
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.7	L;L;L;L;L;L;L;L;L;L;.;.;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;.;D;D;D;D;D;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D;D;D;D;D;.;D;D;D;T;T;T;T;T
Sift4G	Uncertain	0.054	T;T;T;T;T;.;T;T;T;D;.;.;T;.
Polyphen		0.085	B;B;B;B;B;B;B;B;B;B;.;.;.;.
Vest4		0.14
MutPred		0.39		Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);Gain of catalytic residue at S22 (P = 0.0118);
MVP		0.92
MPC		0.054
ClinPred		0.32	T
GERP RS		-5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.093
gMVP		0.31

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: rs199422212; hg19: chr14-94849498;