19-2425948-G-C

Variant names:

• chr19-2425948-G-C
• rs771464310
• NM_001395513.1:c.3142G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001395513.1(TMPRSS9):​c.3142G>C​(p.Ala1048Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,601,374 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TMPRSS9 NM_001395513.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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]

TIMM13 (HGNC:11816): (translocase of inner mitochondrial membrane 13) This gene encodes a member of the evolutionarily conserved TIMM (translocase of inner mitochondrial membrane) family of proteins that function as chaperones in the import of proteins from the cytoplasm into the mitochondrial inner membrane. Proteins of this family play a role in collecting substrate proteins from the translocase of the outer mitochondrial membrane (TOM) complex and delivering them to either the sorting and assembly machinery in the outer mitochondrial membrane (SAM) complex or the TIMM22 complex in the inner mitochondrial membrane. The encoded protein and the translocase of mitochondrial inner membrane 8a protein form a 70 kDa complex in the intermembrane space. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS9	NM_001395513.1	c.3142G>C	p.Ala1048Pro	missense_variant	Exon 19 of 19	ENST00000696167.1	NP_001382442.1
TIMM13	NM_012458.4	c.*1000C>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000215570.8	NP_036590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS9	ENST00000696167.1	c.3142G>C	p.Ala1048Pro	missense_variant	Exon 19 of 19		NM_001395513.1	ENSP00000512457.1
TIMM13	ENST00000215570	c.*1000C>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_012458.4	ENSP00000215570.2
TMPRSS9	ENST00000648592.1	c.3142G>C	p.Ala1048Pro	missense_variant	Exon 18 of 18			ENSP00000498031.1
TMPRSS9	ENST00000649857.1	c.3040G>C	p.Ala1014Pro	missense_variant	Exon 18 of 18			ENSP00000497651.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1449280 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 721110

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152094 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74288

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3040G>C (p.A1014P) alteration is located in exon 17 (coding exon 17) of the TMPRSS9 gene. This alteration results from a G to C substitution at nucleotide position 3040, causing the alanine (A) at amino acid position 1014 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.61	.;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.3	.;.;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0090	.;.;D
Sift4G	Uncertain	0.013	.;.;D
Polyphen		1.0	D;.;D
Vest4		0.85
MutPred		0.76		Gain of catalytic residue at A1014 (P = 0.0107);.;Gain of catalytic residue at A1014 (P = 0.0107);
MVP		0.88
MPC		0.50
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.74

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: rs771464310; hg19: chr19-2425946;