rs139625465

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006351.4(TIMM44):​c.923C>T​(p.Pro308Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TIMM44
NM_006351.4 missense

Scores

9
9
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.41
Variant links:
Genes affected
TIMM44 (HGNC:17316): (translocase of inner mitochondrial membrane 44) This gene encodes a peripheral membrane protein associated with the mitochondrial inner membrane translocase, which functions in the import of proteins across the mitochondrial inner membrane and into the mitochondrial matrix. The encoded protein mediates binding of mitochondrial heat shock protein 70 to the translocase of inner mitochondrial membrane 23 (TIM23) complex. Expression of this gene is upregulated in kidney in a mouse model of diabetes. A mutation in this gene is associated with familial oncocytic thyroid carcinoma. [provided by RefSeq, Jul 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TIMM44NM_006351.4 linkc.923C>T p.Pro308Leu missense_variant Exon 9 of 13 ENST00000270538.8 NP_006342.2 O43615

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TIMM44ENST00000270538.8 linkc.923C>T p.Pro308Leu missense_variant Exon 9 of 13 1 NM_006351.4 ENSP00000270538.2 O43615

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251354
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135878
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461824
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152316
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.42
T;D
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Uncertain
2.3
.;M
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-9.6
.;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0010
.;D
Sift4G
Uncertain
0.039
D;D
Polyphen
0.99
.;D
Vest4
0.97
MutPred
0.92
.;Loss of ubiquitination at K312 (P = 0.1264);
MVP
0.76
MPC
0.79
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139625465; hg19: chr19-7997576; COSMIC: COSV54494573; COSMIC: COSV54494573; API