3-119498746-C-G

Variant names:

• chr3-119498746-C-G
• rs2081843337
• NM_016589.4:c.13C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016589.4(TIMMDC1):​c.13C>G​(p.Pro5Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TIMMDC1 NM_016589.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3870125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMMDC1	NM_016589.4	c.13C>G	p.Pro5Ala	missense_variant	Exon 1 of 7	ENST00000494664.6	NP_057673.2
TIMMDC1	XM_017006556.2	c.13C>G	p.Pro5Ala	missense_variant	Exon 1 of 3		XP_016862045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMMDC1	ENST00000494664.6	c.13C>G	p.Pro5Ala	missense_variant	Exon 1 of 7	1	NM_016589.4	ENSP00000418803.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13C>G (p.P5A) alteration is located in exon 1 (coding exon 1) of the TIMMDC1 gene. This alteration results from a C to G substitution at nucleotide position 13, causing the proline (P) at amino acid position 5 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0014	T;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.026	D;D;D
Sift4G	Benign	0.080	T;D;T
Polyphen		0.88	P;.;.
Vest4		0.37
MutPred		0.45		Loss of glycosylation at P5 (P = 0.0048);Loss of glycosylation at P5 (P = 0.0048);Loss of glycosylation at P5 (P = 0.0048);
MVP		0.38
MPC		0.25
ClinPred		0.91	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.14
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2081843337; hg19: chr3-119217593;