NM_006351.4:c.1354C>A

Variant names:

• chr19-7927192-G-T
• rs758350311
• NM_006351.4:c.1354C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006351.4(TIMM44):​c.1354C>A​(p.Leu452Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,330 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TIMM44 NM_006351.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.40

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM44	NM_006351.4	c.1354C>A	p.Leu452Ile	missense_variant	Exon 13 of 13	ENST00000270538.8	NP_006342.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM44	ENST00000270538.8	c.1354C>A	p.Leu452Ile	missense_variant	Exon 13 of 13	1	NM_006351.4	ENSP00000270538.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000412 AC: 1 AN: 242704 Hom.: 0 AF XY: 0.00000755 AC XY: 1 AN XY: 132478

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456330 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 724778

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0065	T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.22	.;N
REVEL	Uncertain	0.39
Sift	Benign	0.13	.;T
Sift4G	Benign	0.25	T;T
Polyphen		0.95	.;P
Vest4		0.22
MutPred		0.28		.;Loss of helix (P = 0.1299);
MVP		0.43
MPC		1.0
ClinPred		0.95	D
GERP RS		3.6
Varity_R		0.15
gMVP		0.16

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

Other links and lift over

dbSNP: rs758350311; hg19: chr19-7992077; COSMIC: COSV99564337; COSMIC: COSV99564337;