NM_006351.4:c.1038+35delT

Variant names:

• chr19-7931102-TA-T
• rs58157552
• NM_006351.4:c.1038+35delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_006351.4(TIMM44):​c.1038+35delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,237,228 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 30)
  • Exomes 𝑓: 0.11 (0 hom.)
• Consequence: TIMM44 NM_006351.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 19-7931102-TA-T is Benign according to our data. Variant chr19-7931102-TA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1317407.Status of the report is criteria_provided_single_submitter, 1 stars.

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+35delT		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+35delT		intron	N/A	ENSP00000270538.2	O43615
	TIMM44	ENST00000595876.5	TSL:1	n.*726+35delT		intron	N/A	ENSP00000471596.1	M0R124
	TIMM44	ENST00000923643.1		c.1026+35delT		intron	N/A	ENSP00000593702.1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 300 AN: 135812 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00300

Gnomad ASJ AF: 0.00276

Gnomad EAS AF: 0.00128

Gnomad SAS AF: 0.000235

Gnomad FIN AF: 0.00952

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.00211

Gnomad OTH AF: 0.00441

GnomAD2 exomes AF: 0.162 AC: 20477 AN: 126564 AF XY: 0.165

Gnomad AFR exome AF: 0.0839

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.179

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.112 AC: 123699 AN: 1101380 Hom.: 0 Cov.: 0 AF XY: 0.112 AC XY: 61344 AN XY: 548252

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

African (AFR) AF: 0.0841 AC: 2217 AN: 26372

American (AMR) AF: 0.141 AC: 4702 AN: 33444

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 2537 AN: 20198

East Asian (EAS) AF: 0.119 AC: 3580 AN: 30156

South Asian (SAS) AF: 0.120 AC: 7837 AN: 65200

European-Finnish (FIN) AF: 0.107 AC: 4327 AN: 40428

Middle Eastern (MID) AF: 0.0756 AC: 360 AN: 4762

European-Non Finnish (NFE) AF: 0.111 AC: 92844 AN: 834734

Other (OTH) AF: 0.115 AC: 5295 AN: 46086

⚠️ 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: 0.00222 AC: 302 AN: 135848 Hom.: 0 Cov.: 30 AF XY: 0.00245 AC XY: 160 AN XY: 65396

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

African (AFR) AF: 0.000863 AC: 32 AN: 37084

American (AMR) AF: 0.00300 AC: 41 AN: 13672

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 9 AN: 3260

East Asian (EAS) AF: 0.00107 AC: 5 AN: 4678

South Asian (SAS) AF: 0.000236 AC: 1 AN: 4242

European-Finnish (FIN) AF: 0.00952 AC: 74 AN: 7772

Middle Eastern (MID) AF: 0.00365 AC: 1 AN: 274

European-Non Finnish (NFE) AF: 0.00211 AC: 131 AN: 62210

Other (OTH) AF: 0.00438 AC: 8 AN: 1826

⚠️ 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: 0.0664 Hom.: 24

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
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; COSMIC: COSV54491385; COSMIC: COSV54491385;