NM_006351.4:c.1038+34_1038+35dupTT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_006351.4(TIMM44):​c.1038+34_1038+35dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,387,292 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0056 (6 hom., cov: 30)
  • Exomes 𝑓: 0.0036 (0 hom.)
• Consequence: TIMM44 NM_006351.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.175
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00563 (767/136242) while in subpopulation AFR AF = 0.0178 (659/37100). AF 95% confidence interval is 0.0166. There are 6 homozygotes in GnomAd4. There are 373 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 767 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.1038+34_1038+35dupTT		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+35_1038+36insTT		intron	N/A	ENSP00000270538.2	O43615
	TIMM44	ENST00000595876.5	TSL:1	n.*726+35_*726+36insTT		intron	N/A	ENSP00000471596.1	M0R124
	TIMM44	ENST00000923643.1		c.1026+35_1026+36insTT		intron	N/A	ENSP00000593702.1

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 767 AN: 136206 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00245

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000144

Gnomad OTH AF: 0.00659

GnomAD2 exomes AF: 0.00803 AC: 1016 AN: 126564 AF XY: 0.00791

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00621

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00278

Gnomad FIN exome AF: 0.00629

Gnomad NFE exome AF: 0.00599

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00356 AC: 4450 AN: 1251050 Hom.: 0 Cov.: 0 AF XY: 0.00338 AC XY: 2119 AN XY: 626378

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

African (AFR) AF: 0.0205 AC: 587 AN: 28650

American (AMR) AF: 0.00369 AC: 141 AN: 38218

Ashkenazi Jewish (ASJ) AF: 0.00540 AC: 126 AN: 23324

East Asian (EAS) AF: 0.00121 AC: 43 AN: 35414

South Asian (SAS) AF: 0.00273 AC: 212 AN: 77518

European-Finnish (FIN) AF: 0.00334 AC: 159 AN: 47588

Middle Eastern (MID) AF: 0.00307 AC: 16 AN: 5204

European-Non Finnish (NFE) AF: 0.00315 AC: 2966 AN: 942786

Other (OTH) AF: 0.00382 AC: 200 AN: 52348

⚠️ 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: 0.00563 AC: 767 AN: 136242 Hom.: 6 Cov.: 30 AF XY: 0.00568 AC XY: 373 AN XY: 65650

African (AFR) AF: 0.0178 AC: 659 AN: 37100

American (AMR) AF: 0.00568 AC: 78 AN: 13724

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 8 AN: 3268

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

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

European-Finnish (FIN) AF: 0.000127 AC: 1 AN: 7860

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

European-Non Finnish (NFE) AF: 0.000144 AC: 9 AN: 62428

Other (OTH) AF: 0.00655 AC: 12 AN: 1832

Alfa AF: 0.00528 Hom.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs58157552; hg19: chr19-7995987;