rs762492405

Variant names:

• chr19-7927658-G-A
• rs762492405
• NM_006351.4:c.1238C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-7927658-G-A
• chr19-7927658-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_006351.4(TIMM44):​c.1238C>T​(p.Pro413Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000682 in 1,612,976 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P413P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TIMM44 NM_006351.4 missense, splice_region
• Scores: Splicing: ADA: 0.3676
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• BS2: High AC in GnomAdExome4 at 8 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.1238C>T	p.Pro413Leu	missense splice_region	Exon 12 of 13	NP_006342.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM44	ENST00000270538.8	TSL:1 MANE Select	c.1238C>T	p.Pro413Leu	missense splice_region	Exon 12 of 13	ENSP00000270538.2	O43615
	TIMM44	ENST00000923643.1		c.1226C>T	p.Pro409Leu	missense splice_region	Exon 12 of 13	ENSP00000593702.1
	TIMM44	ENST00000870121.1		c.1208C>T	p.Pro403Leu	missense splice_region	Exon 12 of 13	ENSP00000540180.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250436 AF XY: 0.00000738

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460836 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726764

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111840

Other (OTH) AF: 0.0000331 AC: 2 AN: 60382

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152140 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.000196 AC: 3 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.51
Sift	Benign	0.033	D
Sift4G	Uncertain	0.058	T
Polyphen		0.74	P
Vest4		0.53
MutPred		0.70		Loss of disorder (P = 0.0257)
MVP		0.58
MPC		0.69
ClinPred		0.88	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.59
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.37
dbscSNV1_RF	Benign	0.58
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs762492405; hg19: chr19-7992543;