rs781525096

chr3-119515865-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_016589.4(TIMMDC1):c.597-1340A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.00011 (0 hom., cov: 33)
• Consequence: TIMMDC1 NM_016589.4 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.798

Genes affected

TIMMDC1 (HGNC:1321): (translocase of inner mitochondrial membrane domain containing 1) Located in mitochondrion and nucleoplasm. Implicated in nuclear type mitochondrial complex I deficiency 31. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-119515865-A-G is Pathogenic according to our data. Variant chr3-119515865-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 429020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-119515865-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMMDC1	NM_016589.4	c.597-1340A>G		intron_variant		ENST00000494664.6
TIMMDC1	XM_017006556.2	c.195-1340A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMMDC1	ENST00000494664.6	c.597-1340A>G		intron_variant		1	NM_016589.4	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152102 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000107 AC XY: 8 AN XY: 74436

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex 1 deficiency, nuclear type 31 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 25, 2020	The TIMMDC1 c.597-1340A>G variant is a deep intronic variant that has been reported in a homozygous state as c.596+2146A>G in five individuals with mitochondrial complex I deficiency (Kremer et al. 2017). These individuals were from three unrelated families of differing ethnicities. The variant was shown to result in a TIMMDC1 isoform with a new exon insertion in intron 5 that introduces a frameshift and premature stop codon. Patient fibroblasts showed no detectable protein expression and impaired complex I assembly, which could be at least partially restored by expression of wildtype TIMMDC1. In addition to deficient complex I activity in muscle, the affected individuals showed developmental delay, failure to thrive, hypotonia, muscle wasting, dyskinetic movements, cerebellar signs, and peripheral neuropathy. Some individuals showed abnormalities on brain MRI, and one developed acute episodes with abnormal eye movements, myoclonus, and loss of consciousness. The c.597-1340A>G variant is reported at a frequency of 0.000195 in the European (non-Finnish) population of the Genome Aggregation Database in a region of good sequence coverage, indicating it is rare. Based on the collective evidence, the c.597-1340A>G variant is classified as pathogenic for TIMMDC1-related mitochondrial complex I deficiency. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2022	Variant summary: TIMMDC1 (legacy name C3orf1) c.597-1340A>G is located at a deep intronic position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing at the canonical splice sites. However, at least one publication reports RNA sequencing studies that this variant results in the insertion of a poison exon that introduces a frameshift leading to a premature stop codon p.Gly199_Thr200ins5* and thus nonsense mediated decay (NMD) of the aberrant transcript in patient cells (example, Kramer_2017). The variant allele was found at a frequency of 9.6e-05 in 31386 control chromosomes. c.597-1340A>G has been reported in the literature as c.596 + 2146A >G in homozygous and compound heterozygous genotypes in multiple affected individuals from families affected with Mitochondrial Complex 1 Deficiency, Nuclear Type 31 (example, Kremer_2017, Naber_2021, Kumar_2022). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory and the OMIM database have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as pathogenic citing overlapping but not all inclusive evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 13, 2018	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 23, 2023

Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 28604674). The resulting mRNA is expected to undergo nonsense-mediated decay. This sequence change falls in intron 5 of the TIMMDC1 gene. It does not directly change the encoded amino acid sequence of the TIMMDC1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs781525096, gnomAD 0.02%). This variant has been observed in individuals with mitochondrial complex I deficiency (PMID: 28604674, 33278652, 35091571). It has also been observed to segregate with disease in related individuals. This variant is also known as c.596+2146A>G. ClinVar contains an entry for this variant (Variation ID: 429020). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	13
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs781525096; hg19: chr3-119234712;