14-94382724-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000295.5(SERPINA1):c.514G>A(p.Gly172Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,614,258 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G172W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -1.46

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034241676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA1	NM_000295.5	c.514G>A	p.Gly172Arg	missense_variant	2/5	ENST00000393087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA1	ENST00000393087.9	c.514G>A	p.Gly172Arg	missense_variant	2/5	1	NM_000295.5	P1

Frequencies

GnomAD3 genomes AF: 0.00100 AC: 153 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000346 AC: 87 AN: 251480 Hom.: 0 AF XY: 0.000302 AC XY: 41 AN XY: 135914

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000330 AC: 482 AN: 1461892 Hom.: 2 Cov.: 31 AF XY: 0.000329 AC XY: 239 AN XY: 727248

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000286

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74512

Gnomad4 AFR AF: 0.00298

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.000926

ExAC AF: 0.000428 AC: 52

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alpha-1-antitrypsin deficiency Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	curation	Department of Laboratory Medicine and Genetics, Trillium Health Partners Credit Valley Hospital	Dec 08, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	0.019
Dann	Benign	0.33
DEOGEN2	Benign	0.12	T;T;T;T;T;T;T;T;T;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.073	N
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.034	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.56	N;N;N;N;N;N;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.5	N;N;N;N;N;.;N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.93	T;T;T;T;T;.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;.;T;T;T;T;.
Polyphen		0.0	B;B;B;B;B;B;B;B;B;B;.
Vest4		0.12
MutPred		0.69		Gain of catalytic residue at G172 (P = 0.0061);Gain of catalytic residue at G172 (P = 0.0061);Gain of catalytic residue at G172 (P = 0.0061);Gain of catalytic residue at G172 (P = 0.0061);Gain of catalytic residue at G172 (P = 0.0061);Gain of catalytic residue at G172 (P = 0.0061);Gain of catalytic residue at G172 (P = 0.0061);Gain of catalytic residue at G172 (P = 0.0061);Gain of catalytic residue at G172 (P = 0.0061);Gain of catalytic residue at G172 (P = 0.0061);.;
MVP		0.72
MPC		0.050
ClinPred		0.0016	T
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112030253; hg19: chr14-94849061; COSMIC: COSV63345385; COSMIC: COSV63345385;