rs45546534

Positions:

• chr19-2416798-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001395513.1(TMPRSS9):​c.2006A>G​(p.Gln669Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0447 in 1,609,270 control chromosomes in the GnomAD database, including 1,874 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.043 (169 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1705 hom.)
• Consequence: TMPRSS9 NM_001395513.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.562

Genes affected

TMPRSS9 (HGNC:30079): (transmembrane serine protease 9) The protein encoded by this gene is a membrane-bound type II serine polyprotease that is cleaved to release three different proteases. Two of the proteases are active and can be inhibited by serine protease inhibitors, and one is thought to be catalytically inactive. This gene enhances the invasive capability of pancreatic cancer cells and may be involved in cancer progression. [provided by RefSeq, Jul 2016]

LOC124904612 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025051236).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0434 (6603/152260) while in subpopulation NFE AF= 0.0497 (3377/68006). AF 95% confidence interval is 0.0483. There are 169 homozygotes in gnomad4. There are 3284 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 169 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS9	NM_001395513.1	c.2006A>G	p.Gln669Arg	missense_variant	13/19	ENST00000696167.1	NP_001382442.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS9	ENST00000696167.1	c.2006A>G	p.Gln669Arg	missense_variant	13/19		NM_001395513.1	ENSP00000512457.1
TMPRSS9	ENST00000648592.1	c.2006A>G	p.Gln669Arg	missense_variant	12/18			ENSP00000498031.1
TMPRSS9	ENST00000649857.1	c.1904A>G	p.Gln635Arg	missense_variant	12/18			ENSP00000497651.1
TMPRSS9	ENST00000587863.1	n.556A>G		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.0433 AC: 6592 AN: 152142 Hom.: 167 Cov.: 32

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.0717

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0496

Gnomad OTH AF: 0.0436

GnomAD3 exomes AF: 0.0363 AC: 8973 AN: 247026 Hom.: 226 AF XY: 0.0375 AC XY: 5038 AN XY: 134228

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0390

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0449

Gnomad OTH exome AF: 0.0329

GnomAD4 exome AF: 0.0448 AC: 65334 AN: 1457010 Hom.: 1705 Cov.: 32 AF XY: 0.0448 AC XY: 32500 AN XY: 724674

Gnomad4 AFR exome AF: 0.0426

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.00767

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0404

Gnomad4 FIN exome AF: 0.0612

Gnomad4 NFE exome AF: 0.0483

Gnomad4 OTH exome AF: 0.0412

GnomAD4 genome AF: 0.0434 AC: 6603 AN: 152260 Hom.: 169 Cov.: 32 AF XY: 0.0441 AC XY: 3284 AN XY: 74454

Gnomad4 AFR AF: 0.0410

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0350

Gnomad4 FIN AF: 0.0717

Gnomad4 NFE AF: 0.0497

Gnomad4 OTH AF: 0.0422

Alfa AF: 0.0428 Hom.: 179

Bravo AF: 0.0391

TwinsUK AF: 0.0537 AC: 199

ALSPAC AF: 0.0464 AC: 179

ESP6500AA AF: 0.0384 AC: 169

ESP6500EA AF: 0.0420 AC: 361

ExAC AF: 0.0363 AC: 4403

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0443

EpiControl AF: 0.0429

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Benign	0.75
DEOGEN2	Benign	0.097	T;.;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.51	.;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.085	N;.;.;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	.;.;.;N
REVEL	Benign	0.21
Sift	Benign	0.76	.;.;.;T
Sift4G	Benign	0.47	.;.;T;T
Polyphen		0.0090	B;.;.;B
Vest4		0.10, 0.24
MPC		0.085
ClinPred		0.015	T
GERP RS		4.2
Varity_R		0.089
gMVP		0.50

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: rs45546534; hg19: chr19-2416796;