rs774619141

Variant names:

• chr3-119498908-C-G
• rs774619141
• NM_016589.4:c.175C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-119498908-C-G
• chr3-119498908-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016589.4(TIMMDC1):​c.175C>G​(p.Arg59Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TIMMDC1 NM_016589.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• Publications: 3 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 disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 31

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

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

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21445054).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016589.4. 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
	TIMMDC1	NM_016589.4	MANE Select	c.175C>G	p.Arg59Gly	missense	Exon 1 of 7	NP_057673.2	Q9NPL8
	TIMMDC1	NM_001438040.1		c.175C>G	p.Arg59Gly	missense	Exon 1 of 3	NP_001424969.1	C9JU35

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMMDC1	ENST00000494664.6	TSL:1 MANE Select	c.175C>G	p.Arg59Gly	missense	Exon 1 of 7	ENSP00000418803.1	Q9NPL8
	TIMMDC1	ENST00000264244.7	TSL:1	n.175C>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000264244.3	G3XA94
	TIMMDC1	ENST00000854204.1		c.175C>G	p.Arg59Gly	missense	Exon 1 of 7	ENSP00000524263.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250974 AF XY: 0.00

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: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461800 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.016	D
Polyphen		0.32	B
Vest4		0.57
MutPred		0.35		Loss of glycosylation at K64 (P = 0.0722)
MVP		0.35
MPC		0.37
ClinPred		0.89	D
GERP RS		4.0
PromoterAI		-0.077	Neutral
Varity_R		0.24
gMVP		0.68
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs774619141; hg19: chr3-119217755;