chr19-7927658-G-T

Variant names:

• chr19-7927658-G-T
• NM_006351.4:c.1238C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006351.4(TIMM44):​c.1238C>A​(p.Pro413Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TIMM44 NM_006351.4 missense, splice_region
• Scores: Splicing: ADA: 0.3067
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.04

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM44	NM_006351.4	c.1238C>A	p.Pro413Gln	missense_variant, splice_region_variant	Exon 12 of 13	ENST00000270538.8	NP_006342.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM44	ENST00000270538.8	c.1238C>A	p.Pro413Gln	missense_variant, splice_region_variant	Exon 12 of 13	1	NM_006351.4	ENSP00000270538.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460836 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726764

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;T
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	.;L
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.9	.;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.024	.;D
Sift4G	Benign	0.074	T;T
Polyphen		0.83	.;P
Vest4		0.57
MutPred		0.60		.;Loss of ubiquitination at K415 (P = 0.0853);
MVP		0.48
MPC		0.47
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.31
dbscSNV1_RF	Benign	0.34
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-7992543;