chr14-94467358-G-A

Position:

• chr14-94467358-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_175739.4(SERPINA9):​c.653C>T​(p.Pro218Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,610,776 control chromosomes in the GnomAD database, including 78,596 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.28 (6444 hom., cov: 33)
  • Exomes 𝑓: 0.31 (72152 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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00118348).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINA9	NM_175739.4	c.653C>T	p.Pro218Leu	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>T	p.Pro218Leu	missense_variant	3/5		NM_175739.4	ENSP00000501517.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42785 AN: 152048 Hom.: 6440 Cov.: 33

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.296

GnomAD3 exomes AF: 0.319 AC: 79139 AN: 248242 Hom.: 13106 AF XY: 0.320 AC XY: 43134 AN XY: 134596

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.440

Gnomad SAS exome AF: 0.355

Gnomad FIN exome AF: 0.319

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.316

GnomAD4 exome AF: 0.312 AC: 455417 AN: 1458610 Hom.: 72152 Cov.: 35 AF XY: 0.314 AC XY: 227356 AN XY: 724890

Gnomad4 AFR exome AF: 0.163

Gnomad4 AMR exome AF: 0.362

Gnomad4 ASJ exome AF: 0.307

Gnomad4 EAS exome AF: 0.452

Gnomad4 SAS exome AF: 0.352

Gnomad4 FIN exome AF: 0.323

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.314

GnomAD4 genome AF: 0.281 AC: 42817 AN: 152166 Hom.: 6444 Cov.: 33 AF XY: 0.285 AC XY: 21230 AN XY: 74378

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.359

Gnomad4 ASJ AF: 0.299

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.339

Gnomad4 NFE AF: 0.301

Gnomad4 OTH AF: 0.303

Alfa AF: 0.301 Hom.: 16552

Bravo AF: 0.275

TwinsUK AF: 0.307 AC: 1140

ALSPAC AF: 0.319 AC: 1230

ESP6500AA AF: 0.162 AC: 622

ESP6500EA AF: 0.301 AC: 2486

ExAC AF: 0.314 AC: 37964

Asia WGS AF: 0.414 AC: 1440 AN: 3478

EpiCase AF: 0.301

EpiControl AF: 0.299

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.16	.;.;.;.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.69	T;T;T;T;T;T
MetaRNN	Benign	0.0012	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;.;.;.;M;.
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-6.2	D;D;D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.011	D;T;D;D;T;D
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.39	B;P;.;B;B;B
Vest4		0.18
MPC		0.019
ClinPred		0.034	T
GERP RS		1.9
Varity_R		0.19
gMVP		0.31

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: rs17090921; hg19: chr14-94933695; COSMIC: COSV54073248; COSMIC: COSV54073248;