19-2426039-C-T

Position:

• chr19-2426039-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000215570.8(TIMM13):​c.*909G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,609,174 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (43 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (47 hom.)
• Consequence: TIMM13 ENST00000215570.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.02

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011241078).
• BP6: Variant 19-2426039-C-T is Benign according to our data. Variant chr19-2426039-C-T is described in ClinVar as [Benign]. Clinvar id is 783812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1990/152258) while in subpopulation AFR AF= 0.0448 (1860/41520). AF 95% confidence interval is 0.0431. There are 43 homozygotes in gnomad4. There are 979 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS9	NM_001395513.1	c.3233C>T	p.Thr1078Ile	missense_variant	19/19	ENST00000696167.1	NP_001382442.1
TIMM13	NM_012458.4	c.*909G>A		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.3233C>T	p.Thr1078Ile	missense_variant	19/19		NM_001395513.1	ENSP00000512457.1
TIMM13	ENST00000215570.8	c.*909G>A		3_prime_UTR_variant	3/3	1	NM_012458.4	ENSP00000215570.2
TMPRSS9	ENST00000648592.1	c.3233C>T	p.Thr1078Ile	missense_variant	18/18			ENSP00000498031.1
TMPRSS9	ENST00000649857.1	c.3131C>T	p.Thr1044Ile	missense_variant	18/18			ENSP00000497651.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1984 AN: 152140 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00331 AC: 809 AN: 244376 Hom.: 14 AF XY: 0.00241 AC XY: 320 AN XY: 132972

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.000307

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000661

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000374

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00151 AC: 2200 AN: 1456916 Hom.: 47 Cov.: 31 AF XY: 0.00130 AC XY: 941 AN XY: 724904

Gnomad4 AFR exome AF: 0.0460

Gnomad4 AMR exome AF: 0.00305

Gnomad4 ASJ exome AF: 0.000309

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000256

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.0131 AC: 1990 AN: 152258 Hom.: 43 Cov.: 33 AF XY: 0.0131 AC XY: 979 AN XY: 74450

Gnomad4 AFR AF: 0.0448

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00253 Hom.: 7

Bravo AF: 0.0146

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00418 AC: 507

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	.;T;T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.2	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.6	.;.;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	.;.;D
Sift4G	Uncertain	0.0020	.;.;D
Polyphen		1.0	D;.;D
Vest4		0.81
MVP		0.96
MPC		0.45
ClinPred		0.034	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60
gMVP		0.71

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: rs7252121; hg19: chr19-2426037;