14-94467358-G-C

Position:

• chr14-94467358-G-C

Variant summary

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

The NM_175739.4(SERPINA9):​c.653C>G​(p.Pro218Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P218L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SERPINA9 NM_175739.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.581

Genes affected

SERPINA9 (HGNC:15995): (serpin family A member 9) Enables serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be located in cytoplasm and membrane. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

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=0.21600524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA9	NM_175739.4	c.653C>G	p.Pro218Arg	missense_variant	3/5	ENST00000674397.2	NP_783866.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINA9	ENST00000674397.2	c.653C>G	p.Pro218Arg	missense_variant	3/5		NM_175739.4	ENSP00000501517.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458942 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 725070

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.75
DEOGEN2	Benign	0.13	.;.;.;.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.68	T;T;T;T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.9	.;.;.;.;L;.
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;T;D;D;D;T
Sift4G	Benign	0.25	T;T;T;T;T;T
Polyphen		0.22	B;P;.;P;P;B
Vest4		0.28
MutPred		0.55		.;.;.;.;Gain of catalytic residue at P215 (P = 0.0047);.;
MVP		0.82
MPC		0.083
ClinPred		0.77	D
GERP RS		1.9
Varity_R		0.43
gMVP		0.27

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: rs17090921; hg19: chr14-94933695;