14-94382724-C-G

Variant names:

• chr14-94382724-C-G
• NM_000295.5:c.514G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000295.5(SERPINA1):​c.514G>C​(p.Gly172Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G172W) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15823352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINA1	NM_000295.5	c.514G>C	p.Gly172Arg	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.514G>C	p.Gly172Arg	missense_variant	Exon 2 of 5	1	NM_000295.5	ENSP00000376802.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	0.0050
DANN	Benign	0.29
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	0.12	N
LIST_S2	Benign	0.072	.;.;.;T;.;.;.;.;.;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.16	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;.
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		0.033	T
GERP RS		-4.9
Varity_R		0.21
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-94849061;