rs1421119943

Variant names:

• chr14-94467166-A-C
• rs1421119943
• NM_175739.4:c.845T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_175739.4(SERPINA9):​c.845T>G​(p.Leu282Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,866 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SERPINA9 NM_175739.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175739.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA9	NM_175739.4	MANE Select	c.845T>G	p.Leu282Arg	missense	Exon 3 of 5	NP_783866.3	Q86WD7-1
	SERPINA9	NM_001284275.2		c.605T>G	p.Leu202Arg	missense	Exon 3 of 5	NP_001271204.2	Q86WD7-6
	SERPINA9	NM_001042518.2		c.545T>G	p.Leu182Arg	missense	Exon 4 of 6	NP_001035983.2	A0A6Q8JH89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA9	ENST00000674397.2	MANE Select	c.845T>G	p.Leu282Arg	missense	Exon 3 of 5	ENSP00000501517.1	Q86WD7-1
	SERPINA9	ENST00000337425.10	TSL:1	c.899T>G	p.Leu300Arg	missense	Exon 3 of 5	ENSP00000337133.5	Q86WD7-7
	SERPINA9	ENST00000448305.6	TSL:1	c.605T>G	p.Leu202Arg	missense	Exon 3 of 5	ENSP00000414092.2	Q86WD7-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249520 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461866 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		5.6
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.75
MutPred		0.78		Gain of catalytic residue at M279 (P = 0)
MVP		0.98
MPC		0.13
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.94
gMVP		0.60
Mutation Taster		=62/38	polymorphism

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

Other links and lift over

dbSNP: rs1421119943; hg19: chr14-94933503;