NM_006351.4:c.1114A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006351.4(TIMM44):c.1114A>G(p.Ile372Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,613,732 control chromosomes in the GnomAD database, including 1,430 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 120 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1310 hom. )

Consequence

TIMM44
NM_006351.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.77

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]

TIMM44 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031575859).

BP6

Variant 19-7928091-T-C is Benign according to our data. Variant chr19-7928091-T-C is described in ClinVar as [Benign]. Clinvar id is 137647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7928091-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0313 (4770/152294) while in subpopulation NFE AF= 0.0436 (2964/67998). AF 95% confidence interval is 0.0423. There are 120 homozygotes in gnomad4. There are 2441 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 120 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM44	NM_006351.4 link	c.1114A>G	p.Ile372Val	missense_variant	Exon 11 of 13	ENST00000270538.8	NP_006342.2	O43615

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM44	ENST00000270538.8 link	c.1114A>G	p.Ile372Val	missense_variant	Exon 11 of 13	1	NM_006351.4	ENSP00000270538.2		O43615

Frequencies

GnomAD3 genomes

AF:

0.0313

AC:

4770

AN:

152176

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00717

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0244

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0149

Gnomad FIN

AF:

0.0832

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0436

Gnomad OTH

AF:

0.0344

GnomAD3 exomes

AF:

0.0310

AC:

7753

AN:

249788

Hom.:

161

AF XY:

0.0319

AC XY:

4316

AN XY:

135446

show subpopulations

Gnomad AFR exome

AF:

0.00602

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.0376

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0136

Gnomad FIN exome

AF:

0.0736

Gnomad NFE exome

AF:

0.0408

Gnomad OTH exome

AF:

0.0354

GnomAD4 exome

AF:

0.0386

AC:

56470

AN:

1461438

Hom.:

1310

Cov.:

AF XY:

0.0382

AC XY:

27757

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.00550

Gnomad4 AMR exome

AF:

0.0145

Gnomad4 ASJ exome

AF:

0.0374

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0145

Gnomad4 FIN exome

AF:

0.0712

Gnomad4 NFE exome

AF:

0.0427

Gnomad4 OTH exome

AF:

0.0331

GnomAD4 genome

AF:

0.0313

AC:

4770

AN:

152294

Hom.:

120

Cov.:

AF XY:

0.0328

AC XY:

2441

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00714

Gnomad4 AMR

AF:

0.0243

Gnomad4 ASJ

AF:

0.0288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0149

Gnomad4 FIN

AF:

0.0832

Gnomad4 NFE

AF:

0.0436

Gnomad4 OTH

AF:

0.0345

Alfa

AF:

0.0375

Hom.:

103

Bravo

AF:

0.0258

TwinsUK

AF:

0.0418

AC:

155

ALSPAC

AF:

0.0374

AC:

144

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.0448

AC:

385

ExAC

AF:

0.0296

AC:

3586

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0408

EpiControl

AF:

0.0417

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Oct 24, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.11

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.88

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.52

REVEL

Benign

0.21

Sift

Benign

0.26

Sift4G

Benign

0.33

Polyphen

0.0020

Vest4

0.068

MPC

0.31

ClinPred

0.0025

GERP RS

2.5

Varity_R

0.096

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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