NM_006351.4:c.1128+3A>G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM44	NM_006351.4	c.1128+3A>G		splice_region_variant, intron_variant	Intron 11 of 12	ENST00000270538.8	NP_006342.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM44	ENST00000270538.8	c.1128+3A>G		splice_region_variant, intron_variant	Intron 11 of 12	1	NM_006351.4	ENSP00000270538.2

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

GnomAD3 exomes AF: 0.0631 AC: 15660 AN: 248276 Hom.: 498 AF XY: 0.0626 AC XY: 8428 AN XY: 134694

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 SAS exome AF: 0.0541

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

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0386

Gnomad4 ASJ exome AF: 0.0706

Gnomad4 EAS exome AF: 0.0484

Gnomad4 SAS exome AF: 0.0563

Gnomad4 FIN exome AF: 0.0708

Gnomad4 NFE exome AF: 0.0717

Gnomad4 OTH exome AF: 0.0700

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

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.0602

Gnomad4 ASJ AF: 0.0732

Gnomad4 EAS AF: 0.0433

Gnomad4 SAS AF: 0.0478

Gnomad4 FIN AF: 0.0666

Gnomad4 NFE AF: 0.0719

Gnomad4 OTH AF: 0.0776

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Jan 09, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.8
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs34425383; hg19: chr19-7992959;