3-119498909-G-A

Position:

• chr3-119498909-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_016589.4(TIMMDC1):​c.176G>A​(p.Arg59Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: TIMMDC1 NM_016589.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033982337).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000368 (56/152136) while in subpopulation NFE AF= 0.00072 (49/68026). AF 95% confidence interval is 0.00056. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMMDC1	NM_016589.4	c.176G>A	p.Arg59Gln	missense_variant	1/7	ENST00000494664.6	NP_057673.2
TIMMDC1	XM_017006556.2	c.176G>A	p.Arg59Gln	missense_variant	1/3		XP_016862045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMMDC1	ENST00000494664.6	c.176G>A	p.Arg59Gln	missense_variant	1/7	1	NM_016589.4	ENSP00000418803.1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000335 AC: 84 AN: 250960 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135852

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000643

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000534 AC: 780 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.000480 AC XY: 349 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000658

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74324

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000590 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TIMMDC1 protein function. This variant has not been reported in the literature in individuals affected with TIMMDC1-related conditions. This variant is present in population databases (rs142917333, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 59 of the TIMMDC1 protein (p.Arg59Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0042	T;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0070	B;.;.
Vest4		0.24
MVP		0.17
MPC		0.19
ClinPred		0.064	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.52

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: rs142917333; hg19: chr3-119217756;