3-119517281-C-T

Variant names:

• chr3-119517281-C-T
• rs149481081
• NM_016589.4:c.673C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_016589.4(TIMMDC1):​c.673C>T​(p.Arg225*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TIMMDC1 NM_016589.4 stop_gained
• Clinical Significance: - - U:1
• Conservation: PhyloP100: 0.665
• Publications: 5 publications found

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]

TIMMDC1 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 31

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae)
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.216 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMMDC1	NM_016589.4	c.673C>T	p.Arg225*	stop_gained	Exon 6 of 7	ENST00000494664.6	NP_057673.2
TIMMDC1	NM_001438040.1	c.271C>T	p.Arg91*	stop_gained	Exon 2 of 3		NP_001424969.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMMDC1	ENST00000494664.6	c.673C>T	p.Arg225*	stop_gained	Exon 6 of 7	1	NM_016589.4	ENSP00000418803.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251250 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461206 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 726950

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111512

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000300 Hom.: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: -

Submissions summary: Uncertain:1

Revision: -

Submissions by phenotype

Leigh syndrome Uncertain:1

Jan 07, 2019

Mitochondrial Research Group, Murdoch Children's Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

We have identified a homozygous variant within TIMMDC1 (Gene ID: 51300) in an individual with Leigh-like syndrome. This variant creates a premature stop codon, and causes C-terminal truncation of 61 amino acids, p.Arg225*. Western blotting of fibroblasts from the patient confirmed that the variant produces a stable truncated protein. BN-PAGE studies on patient fibroblasts showed that the steady-state level of assembled complex I was mildly reduced relative to control. Spectrophotometric analysis of OXPHOS enzymes demonstrated that complex I activity in patient fibroblasts was within the control reference range. Complementation studies using TIMMDC1 knockout HEK293T cells showed that overexpression of the TIMMDC1 p.(Arg225*) mutant was able to rescue a complex I assembly defect in the TIMMDC1 knockout cells equally as well as overexpression of wild-type protein. Examination of TIMMDC1 variants reported in gnomAD revealed that 50% of all nonsense and frameshift variants lay downstream of the p.(Arg225*) variant in the last 20% of the coding region, implying that the C-terminus of TIMMDC1 is enriched with protein-truncating variants at a population level. An alternate molecular basis for disease was identified in the patient. The data were initially interpreted to support a likely benign impact of the variant. However, following reviewer feedback on a manuscript we regard the evidence of a hypomorphic effect on some subunits, and limitations of overexpression studies to rescue phenotype, mean it is appropriate to reclassify the variant as a VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	0.039
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.062	N
PhyloP100		0.67
Vest4		0.17
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=60/140	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs149481081; hg19: chr3-119236128; COSMIC: COSV51785922; COSMIC: COSV51785922;