19-7932691-G-T

Variant names:

• chr19-7932691-G-T
• rs139625465
• NM_006351.4:c.923C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP4_Moderate BS2

The NM_006351.4(TIMM44):​c.923C>A​(p.Pro308Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,614,140 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. P308P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (13 hom.)
• Consequence: TIMM44 NM_006351.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.41

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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.097957134).
• BS2: High Homozygotes in GnomAdExome4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM44	NM_006351.4	c.923C>A	p.Pro308Gln	missense_variant	Exon 9 of 13	ENST00000270538.8	NP_006342.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM44	ENST00000270538.8	c.923C>A	p.Pro308Gln	missense_variant	Exon 9 of 13	1	NM_006351.4	ENSP00000270538.2

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 448 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00273 AC: 687 AN: 251354 AF XY: 0.00270

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00442

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00443 AC: 6479 AN: 1461824 Hom.: 13 Cov.: 31 AF XY: 0.00429 AC XY: 3120 AN XY: 727220

Gnomad4 AFR exome AF: 0.00105 AC: 35 AN: 33480

Gnomad4 AMR exome AF: 0.00329 AC: 147 AN: 44720

Gnomad4 ASJ exome AF: 0.0000383 AC: 1 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.000638 AC: 55 AN: 86258

Gnomad4 FIN exome AF: 0.000262 AC: 14 AN: 53366

Gnomad4 NFE exome AF: 0.00540 AC: 6003 AN: 1112000

Gnomad4 Remaining exome AF: 0.00369 AC: 223 AN: 60396

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.00266 AC XY: 198 AN XY: 74478

Gnomad4 AFR AF: 0.00152 AC: 0.00151559 AN: 0.00151559

Gnomad4 AMR AF: 0.00222 AC: 0.00222106 AN: 0.00222106

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00124 AC: 0.00124224 AN: 0.00124224

Gnomad4 FIN AF: 0.000471 AC: 0.000470633 AN: 0.000470633

Gnomad4 NFE AF: 0.00475 AC: 0.00474818 AN: 0.00474818

Gnomad4 OTH AF: 0.00189 AC: 0.00189215 AN: 0.00189215

Alfa AF: 0.00393 Hom.: 4

Bravo AF: 0.00299

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00270 AC: 328

EpiCase AF: 0.00414

EpiControl AF: 0.00492

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Likely pathogenic and reported on 04-21-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.2	.;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.6	.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.94
MVP		0.75
MPC		1.1
ClinPred		0.089	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.77
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs139625465; hg19: chr19-7997576; COSMIC: COSV99563775; COSMIC: COSV99563775;