19-7928091-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

thyroid cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TIMM44 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 137647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 4770 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006351.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM44	NM_006351.4	MANE Select	c.1114A>G	p.Ile372Val	missense	Exon 11 of 13	NP_006342.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIMM44	ENST00000270538.8	TSL:1 MANE Select	c.1114A>G	p.Ile372Val	missense	Exon 11 of 13	ENSP00000270538.2	O43615
TIMM44	ENST00000923643.1		c.1102A>G	p.Ile368Val	missense	Exon 11 of 13	ENSP00000593702.1
TIMM44	ENST00000870121.1		c.1084A>G	p.Ile362Val	missense	Exon 11 of 13	ENSP00000540180.1

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

GnomAD2 exomes

AF:

0.0310

AC:

7753

AN:

249788

AF XY:

0.0319

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 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

African (AFR)

AF:

0.00550

AC:

184

AN:

33478

American (AMR)

AF:

0.0145

AC:

647

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0374

AC:

977

AN:

26118

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0145

AC:

1251

AN:

86232

European-Finnish (FIN)

AF:

0.0712

AC:

3795

AN:

53320

Middle Eastern (MID)

AF:

0.0255

AC:

147

AN:

5768

European-Non Finnish (NFE)

AF:

0.0427

AC:

47472

AN:

1111750

Other (OTH)

AF:

0.0331

AC:

1996

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2621

5242

7863

10484

13105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1682

3364

5046

6728

8410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0313

AC:

4770

AN:

152294

Hom.:

120

Cov.:

AF XY:

0.0328

AC XY:

2441

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00714

AC:

297

AN:

41568

American (AMR)

AF:

0.0243

AC:

372

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

100

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0149

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0832

AC:

883

AN:

10618

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0436

AC:

2964

AN:

67998

Other (OTH)

AF:

0.0345

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

258

516

773

1031

1289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0380

Hom.:

307

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

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

PhyloP100

2.8

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

Mutation Taster

=79/21

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over