14-94378613-C-G

Variant names:

• chr14-94378613-C-G
• rs143370956
• NM_000295.5:c.1093G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000295.5(SERPINA1):​c.1093G>C​(p.Asp365His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D365N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.1093G>C	p.Asp365His	missense_variant	Exon 5 of 5	ENST00000393087.9	NP_000286.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINA1	ENST00000393087.9	c.1093G>C	p.Asp365His	missense_variant	Exon 5 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251350 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135850

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: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.0000248 AC XY: 18 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SERPINA1 c.1093G>C (p.Asp365His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251350 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1093G>C in individuals affected with Alpha-1-Antitrypsin Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;D;D;D;D;D;D;D;D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.79	.;.;.;T;.;.;.;.;.
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;M;M;M;M;M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;.;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.20	T;T;T;T;T;.;T;T;T
Sift4G	Benign	0.19	T;T;T;T;T;.;T;T;T
Polyphen		0.91	P;P;P;P;P;P;P;P;P
Vest4		0.21
MutPred		0.66		Gain of catalytic residue at T369 (P = 0.0436);Gain of catalytic residue at T369 (P = 0.0436);Gain of catalytic residue at T369 (P = 0.0436);Gain of catalytic residue at T369 (P = 0.0436);Gain of catalytic residue at T369 (P = 0.0436);Gain of catalytic residue at T369 (P = 0.0436);Gain of catalytic residue at T369 (P = 0.0436);Gain of catalytic residue at T369 (P = 0.0436);Gain of catalytic residue at T369 (P = 0.0436);
MVP		1.0
MPC		0.27
ClinPred		0.74	D
GERP RS		3.0
Varity_R		0.32
gMVP		0.60

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: rs143370956; hg19: chr14-94844950;