rs45546534

Variant names:

• chr19-2416798-A-G
• rs45546534
• NM_001395513.1:c.2006A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 10 publications found

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]

TMPRSS9 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

LOC124904612 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 169 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS9	NM_001395513.1	c.2006A>G	p.Gln669Arg	missense_variant	Exon 13 of 19	ENST00000696167.1	NP_001382442.1

Ensembl

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

GnomAD2 exomes AF: 0.0363 AC: 8973 AN: 247026 AF XY: 0.0375

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 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

African (AFR) AF: 0.0426 AC: 1426 AN: 33462

American (AMR) AF: 0.0184 AC: 823 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00767 AC: 200 AN: 26060

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39672

South Asian (SAS) AF: 0.0404 AC: 3486 AN: 86196

European-Finnish (FIN) AF: 0.0612 AC: 3057 AN: 49976

Middle Eastern (MID) AF: 0.0283 AC: 163 AN: 5758

European-Non Finnish (NFE) AF: 0.0483 AC: 53691 AN: 1110916

Other (OTH) AF: 0.0412 AC: 2485 AN: 60298

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

African (AFR) AF: 0.0410 AC: 1704 AN: 41560

American (AMR) AF: 0.0271 AC: 414 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0350 AC: 169 AN: 4824

European-Finnish (FIN) AF: 0.0717 AC: 761 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0497 AC: 3377 AN: 68006

Other (OTH) AF: 0.0422 AC: 89 AN: 2110

Alfa AF: 0.0429 Hom.: 287

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
PhyloP100		0.56
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
Mutation Taster		=98/2	polymorphism (auto)

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: rs45546534; hg19: chr19-2416796; COSMIC: COSV107406347; COSMIC: COSV107406347;