20-44955212-G-A

Position:

chr20-44955212-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006809.5(TOMM34):c.236C>T(p.Ala79Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

TOMM34
NM_006809.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.694

Variant links:

Genes affected

TOMM34 (HGNC:15746): (translocase of outer mitochondrial membrane 34) The protein encoded by this gene is involved in the import of precursor proteins into mitochondria. The encoded protein has a chaperone-like activity, binding the mature portion of unfolded proteins and aiding their import into mitochondria. This protein, which is found in the cytoplasm and sometimes associated with the outer mitochondrial membrane, has a weak ATPase activity and contains 6 TPR repeats. [provided by RefSeq, Jul 2008]

TOMM34 links:

PABPC1L (HGNC:15797): (poly(A) binding protein cytoplasmic 1 like) This gene belongs to the polyadenylate-binding protein type-1 family of proteins. Members of this family bind to the polyA tails of mRNAs to regulate mRNA stability and translation. The mouse ortholog of this gene is required for female fertility. In human, expression of a functional protein is regulated by alternative splicing. The protein-coding splice variant for this gene is abundantly expressed in human oocytes, while a noncoding splice variant subject to nonsense-mediated decay is the predominant splice variant expressed in somatic tissues. [provided by RefSeq, Aug 2019]

PABPC1L links:

LOC124904912 (HGNC:):

LOC124904912 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.12015286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TOMM34	NM_006809.5 linkuse as main transcript	c.236C>T	p.Ala79Val	missense_variant	3/7	ENST00000372813.4	NP_006800.2
TOMM34	XM_011528501.2 linkuse as main transcript	c.158C>T	p.Ala53Val	missense_variant	3/7		XP_011526803.1
TOMM34	XM_017027600.3 linkuse as main transcript	c.236C>T	p.Ala79Val	missense_variant	3/5		XP_016883089.1
LOC124904912	XR_007067599.1 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMM34	ENST00000372813.4 linkuse as main transcript	c.236C>T	p.Ala79Val	missense_variant	3/7	1	NM_006809.5	ENSP00000361900	P1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000916

AC:

AN:

250982

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

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:

0.000167

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000162

AC:

237

AN:

1461676

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000193

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000131

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000988

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000119

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 submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.236C>T (p.A79V) alteration is located in exon 3 (coding exon 3) of the TOMM34 gene. This alteration results from a C to T substitution at nucleotide position 236, causing the alanine (A) at amino acid position 79 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.17

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.46

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.38

M_CAP

Benign

0.028

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.3

REVEL

Benign

0.036

Sift

Benign

0.033

Sift4G

Uncertain

0.019

Polyphen

0.024

Vest4

0.20

MVP

0.27

MPC

0.51

ClinPred

0.061

GERP RS

-0.22

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over