rs149481081

Positions:

• chr3-119517281-C-G
• chr3-119517281-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016589.4(TIMMDC1):​c.673C>G​(p.Arg225Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. R225Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TIMMDC1 NM_016589.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.665

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09768438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMMDC1	NM_016589.4	c.673C>G	p.Arg225Gly	missense_variant	6/7	ENST00000494664.6
TIMMDC1	XM_017006556.2	c.271C>G	p.Arg91Gly	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMMDC1	ENST00000494664.6	c.673C>G	p.Arg225Gly	missense_variant	6/7	1	NM_016589.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251250 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135772

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461206 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726950

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: 0.0000187

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.098	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0070	D;D;T
Polyphen		0.50	P;.;.
Vest4		0.41
MutPred		0.44		Loss of MoRF binding (P = 0.0165);.;.;
MVP		0.31
MPC		0.35
ClinPred		0.28	T
GERP RS		3.0
Varity_R		0.23
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs149481081; hg19: chr3-119236128;