19-7931102-TAAAAAA-TAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006351.4(TIMM44):​c.1038+35dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 135,820 control chromosomes in the GnomAD database, including 936 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (936 hom., cov: 30)
  • Exomes 𝑓: 0.24 (184 hom.)
  • Failed GnomAD Quality Control
• Consequence: TIMM44 NM_006351.4 intron
• Clinical Significance: 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 19-7931102-T-TA is Benign according to our data. Variant chr19-7931102-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1291438.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.19 is higher than 0.05.

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+35dupT		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+36insT		intron	N/A	ENSP00000270538.2	O43615
	TIMM44	ENST00000595876.5	TSL:1	n.*726+35_*726+36insT		intron	N/A	ENSP00000471596.1	M0R124
	TIMM44	ENST00000923643.1		c.1026+35_1026+36insT		intron	N/A	ENSP00000593702.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 15327 AN: 135788 Hom.: 932 Cov.: 30

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0940

Gnomad AMR AF: 0.0849

Gnomad ASJ AF: 0.0843

Gnomad EAS AF: 0.0451

Gnomad SAS AF: 0.0551

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.0777

Gnomad NFE AF: 0.0852

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.268 AC: 33904 AN: 126564 AF XY: 0.271

Gnomad AFR exome AF: 0.332

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.289

Gnomad EAS exome AF: 0.250

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.280

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.242 AC: 261280 AN: 1078312 Hom.: 184 Cov.: 0 AF XY: 0.241 AC XY: 129328 AN XY: 536670

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

African (AFR) AF: 0.297 AC: 7748 AN: 26086

American (AMR) AF: 0.195 AC: 6471 AN: 33216

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 4862 AN: 20030

East Asian (EAS) AF: 0.221 AC: 6506 AN: 29470

South Asian (SAS) AF: 0.213 AC: 13573 AN: 63658

European-Finnish (FIN) AF: 0.236 AC: 9548 AN: 40524

Middle Eastern (MID) AF: 0.206 AC: 970 AN: 4712

European-Non Finnish (NFE) AF: 0.246 AC: 200465 AN: 815500

Other (OTH) AF: 0.247 AC: 11137 AN: 45116

⚠️ 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: 0.113 AC: 15348 AN: 135820 Hom.: 936 Cov.: 30 AF XY: 0.113 AC XY: 7401 AN XY: 65408

African (AFR) AF: 0.194 AC: 7174 AN: 37028

American (AMR) AF: 0.0848 AC: 1161 AN: 13690

Ashkenazi Jewish (ASJ) AF: 0.0843 AC: 275 AN: 3262

East Asian (EAS) AF: 0.0453 AC: 212 AN: 4680

South Asian (SAS) AF: 0.0549 AC: 233 AN: 4242

European-Finnish (FIN) AF: 0.0863 AC: 671 AN: 7776

Middle Eastern (MID) AF: 0.0803 AC: 22 AN: 274

European-Non Finnish (NFE) AF: 0.0852 AC: 5300 AN: 62220

Other (OTH) AF: 0.122 AC: 222 AN: 1818

Alfa AF: 0.0971 Hom.: 24

ClinVar

ClinVar submissions

Significance: 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 (auto)

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: COSV104374264; COSMIC: COSV104374264;