11-112086722-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_012459.4(TIMM8B):ā€‹c.2T>Cā€‹(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000811 in 1,602,506 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000062 ( 1 hom. )

Consequence

TIMM8B
NM_012459.4 start_lost

Scores

3
6
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.15
Variant links:
Genes affected
TIMM8B (HGNC:11818): (translocase of inner mitochondrial membrane 8 homolog B) This gene encodes a member of a well-conserved family of proteins with similarity to yeast Tim mitochondrial import proteins. This gene is encoded by a nuclear gene and is transported into the intermembrane space of the mitochondrion. When formed into complexes, these proteins guide membrane-spanning proteins across the mitochondrial intermembrane space before they are added into the mitochondrial inner membrane. This gene is adjacent to succinate dehydrogenase, subunit D (SDHD), in which mutations have been found in affected members of families with hereditary paraganglioma.[provided by RefSeq, Aug 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TIMM8BNM_012459.4 linkc.2T>C p.Met1? start_lost 1/2 ENST00000504148.3 NP_036591.3 Q9Y5J9G3XAN8
TIMM8BNR_028383.2 linkn.35T>C non_coding_transcript_exon_variant 1/3
TIMM8BNR_160400.1 linkn.35T>C non_coding_transcript_exon_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TIMM8BENST00000504148.3 linkc.2T>C p.Met1? start_lost 1/21 NM_012459.4 ENSP00000422122.2 Q9Y5J9
TIMM8BENST00000541231.1 linkc.47T>C p.Met16Thr missense_variant 1/21 ENSP00000438455.1 G3XAN8
TIMM8BENST00000509359.6 linkn.2T>C non_coding_transcript_exon_variant 1/31 ENSP00000421964.2 E9PIR3
TIMM8BENST00000507614.1 linkn.1T>C non_coding_transcript_exon_variant 1/33

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000130
AC:
3
AN:
230978
Hom.:
0
AF XY:
0.00000797
AC XY:
1
AN XY:
125416
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000303
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000953
Gnomad OTH exome
AF:
0.000174
GnomAD4 exome
AF:
0.00000621
AC:
9
AN:
1450316
Hom.:
1
Cov.:
32
AF XY:
0.00000416
AC XY:
3
AN XY:
721090
show subpopulations
Gnomad4 AFR exome
AF:
0.0000599
Gnomad4 AMR exome
AF:
0.0000458
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000499
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000121
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 18, 2023The c.47T>C (p.M16T) alteration is located in exon 1 (coding exon 1) of the TIMM8B gene. This alteration results from a T to C substitution at nucleotide position 47, causing the methionine (M) at amino acid position 16 to be replaced by a threonine (T). 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
BayesDel_addAF
Uncertain
0.013
T
BayesDel_noAF
Benign
-0.13
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.090
T;T
Eigen
Benign
-0.065
Eigen_PC
Benign
0.072
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.90
D;T
M_CAP
Pathogenic
0.76
D
MetaRNN
Pathogenic
0.76
D;D
MetaSVM
Benign
-0.56
T
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.49
N;N
REVEL
Uncertain
0.35
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0090
D;D
Polyphen
0.0
B;.
Vest4
0.74
MVP
0.93
MPC
0.048
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.95
gMVP
0.41

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

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

Other links and lift over

dbSNP: rs756774737; hg19: chr11-111957446; API