19-2425963-T-G

Position:

• chr19-2425963-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000215570.8(TIMM13):​c.*985A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TIMM13 ENST00000215570.8 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16215214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS9	NM_001395513.1	c.3157T>G	p.Ser1053Ala	missense_variant	19/19	ENST00000696167.1	NP_001382442.1
TIMM13	NM_012458.4	c.*985A>C		3_prime_UTR_variant	3/3	ENST00000215570.8	NP_036590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS9	ENST00000696167.1	c.3157T>G	p.Ser1053Ala	missense_variant	19/19		NM_001395513.1	ENSP00000512457.1
TIMM13	ENST00000215570.8	c.*985A>C		3_prime_UTR_variant	3/3	1	NM_012458.4	ENSP00000215570.2
TMPRSS9	ENST00000648592.1	c.3157T>G	p.Ser1053Ala	missense_variant	18/18			ENSP00000498031.1
TMPRSS9	ENST00000649857.1	c.3055T>G	p.Ser1019Ala	missense_variant	18/18			ENSP00000497651.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453954 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723504

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.3055T>G (p.S1019A) alteration is located in exon 17 (coding exon 17) of the TMPRSS9 gene. This alteration results from a T to G substitution at nucleotide position 3055, causing the serine (S) at amino acid position 1019 to be replaced by an alanine (A). 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	Benign	0.096
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.098	T;.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.63	.;T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Uncertain	0.025	D
MutationAssessor	Benign	1.3	L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	.;.;N
REVEL	Benign	0.27
Sift	Benign	0.14	.;.;T
Sift4G	Benign	0.073	.;.;T
Polyphen		0.27	B;.;B
Vest4		0.29
MutPred		0.40		Loss of phosphorylation at S1019 (P = 0.0637);.;Loss of phosphorylation at S1019 (P = 0.0637);
MVP		0.77
MPC		0.18
ClinPred		0.49	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.091
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-2425961;