rs34425383

Variant names:

• chr19-7928074-T-C
• rs34425383
• NM_006351.4:c.1128+3A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006351.4(TIMM44):​c.1128+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0709 in 1,612,756 control chromosomes in the GnomAD database, including 4,228 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (515 hom., cov: 33)
  • Exomes 𝑓: 0.070 (3713 hom.)
• Consequence: TIMM44 NM_006351.4 splice_region, intron
• Scores: Splicing: ADA: 0.002675
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0120
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 19-7928074-T-C is Benign according to our data. Variant chr19-7928074-T-C is described in ClinVar as Benign. ClinVar VariationId is 137648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 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.1128+3A>G		splice_region 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.1128+3A>G		splice_region intron	N/A	ENSP00000270538.2	O43615
	TIMM44	ENST00000923643.1		c.1116+3A>G		splice_region intron	N/A	ENSP00000593702.1
	TIMM44	ENST00000870121.1		c.1098+3A>G		splice_region intron	N/A	ENSP00000540180.1

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12137 AN: 152172 Hom.: 514 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0603

Gnomad ASJ AF: 0.0732

Gnomad EAS AF: 0.0432

Gnomad SAS AF: 0.0480

Gnomad FIN AF: 0.0666

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0719

Gnomad OTH AF: 0.0784

GnomAD2 exomes AF: 0.0631 AC: 15660 AN: 248276 AF XY: 0.0626

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.0372

Gnomad ASJ exome AF: 0.0708

Gnomad EAS exome AF: 0.0369

Gnomad FIN exome AF: 0.0723

Gnomad NFE exome AF: 0.0683

Gnomad OTH exome AF: 0.0628

GnomAD4 exome AF: 0.0700 AC: 102225 AN: 1460466 Hom.: 3713 Cov.: 31 AF XY: 0.0694 AC XY: 50455 AN XY: 726520

African (AFR) AF: 0.111 AC: 3719 AN: 33446

American (AMR) AF: 0.0386 AC: 1722 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 1843 AN: 26114

East Asian (EAS) AF: 0.0484 AC: 1921 AN: 39662

South Asian (SAS) AF: 0.0563 AC: 4852 AN: 86156

European-Finnish (FIN) AF: 0.0708 AC: 3770 AN: 53274

Middle Eastern (MID) AF: 0.0828 AC: 477 AN: 5764

European-Non Finnish (NFE) AF: 0.0717 AC: 79701 AN: 1111082

Other (OTH) AF: 0.0700 AC: 4220 AN: 60314

GnomAD4 genome AF: 0.0798 AC: 12146 AN: 152290 Hom.: 515 Cov.: 33 AF XY: 0.0788 AC XY: 5873 AN XY: 74502

African (AFR) AF: 0.112 AC: 4668 AN: 41558

American (AMR) AF: 0.0602 AC: 922 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0732 AC: 254 AN: 3472

East Asian (EAS) AF: 0.0433 AC: 224 AN: 5178

South Asian (SAS) AF: 0.0478 AC: 231 AN: 4830

European-Finnish (FIN) AF: 0.0666 AC: 708 AN: 10626

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0719 AC: 4887 AN: 67992

Other (OTH) AF: 0.0776 AC: 164 AN: 2114

Alfa AF: 0.0743 Hom.: 185

Bravo AF: 0.0781

Asia WGS AF: 0.0490 AC: 172 AN: 3478

EpiCase AF: 0.0724

EpiControl AF: 0.0713

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.8
DANN	Benign	0.48
PhyloP100		-0.012
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0027
dbscSNV1_RF	Benign	0.036
SpliceAI score (max)		0.11		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: rs34425383; hg19: chr19-7992959; COSMIC: COSV107213957; COSMIC: COSV107213957;