19-7931102-TAAAAAA-TAAAA

Variant names:

• chr19-7931102-TAA-T
• rs58157552
• NM_006351.4:c.1038+34_1038+35delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006351.4(TIMM44):​c.1038+34_1038+35delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000659 in 1,384,386 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: TIMM44 NM_006351.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.475
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.1038+34_1038+35delTT		intron	N/A	NP_006342.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM44	ENST00000270538.8	TSL:1 MANE Select	c.1038+34_1038+35delTT		intron	N/A	ENSP00000270538.2	O43615
	TIMM44	ENST00000595876.5	TSL:1	n.*726+34_*726+35delTT		intron	N/A	ENSP00000471596.1	M0R124
	TIMM44	ENST00000923643.1		c.1026+34_1026+35delTT		intron	N/A	ENSP00000593702.1

Frequencies

GnomAD3 genomes AF: 0.0000367 AC: 5 AN: 136142 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000730

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000383

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000160

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00152 AC: 193 AN: 126564 AF XY: 0.00151

Gnomad AFR exome AF: 0.000638

Gnomad AMR exome AF: 0.00259

Gnomad ASJ exome AF: 0.00125

Gnomad EAS exome AF: 0.00205

Gnomad FIN exome AF: 0.000850

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.000638

GnomAD4 exome AF: 0.000727 AC: 907 AN: 1248208 Hom.: 0 AF XY: 0.000665 AC XY: 416 AN XY: 625158

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000976 AC: 28 AN: 28684

American (AMR) AF: 0.00195 AC: 74 AN: 37950

Ashkenazi Jewish (ASJ) AF: 0.000471 AC: 11 AN: 23374

East Asian (EAS) AF: 0.000452 AC: 16 AN: 35364

South Asian (SAS) AF: 0.000424 AC: 33 AN: 77750

European-Finnish (FIN) AF: 0.000462 AC: 22 AN: 47584

Middle Eastern (MID) AF: 0.000576 AC: 3 AN: 5210

European-Non Finnish (NFE) AF: 0.000718 AC: 675 AN: 940052

Other (OTH) AF: 0.000861 AC: 45 AN: 52240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000367 AC: 5 AN: 136178 Hom.: 0 Cov.: 30 AF XY: 0.0000457 AC XY: 3 AN XY: 65612

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 37094

American (AMR) AF: 0.0000729 AC: 1 AN: 13716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3264

East Asian (EAS) AF: 0.00 AC: 0 AN: 4682

South Asian (SAS) AF: 0.00 AC: 0 AN: 4244

European-Finnish (FIN) AF: 0.000383 AC: 3 AN: 7836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.0000160 AC: 1 AN: 62408

Other (OTH) AF: 0.00 AC: 0 AN: 1830

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00262 Hom.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs58157552; hg19: chr19-7995987;