3-119500732-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016589.4(TIMMDC1):c.232T>C(p.Cys78Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,060 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (12 hom., cov: 33)
  • Exomes 𝑓: 0.011 (138 hom.)
• Consequence: TIMMDC1 NM_016589.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.86

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004440844).
• BP6: Variant 3-119500732-T-C is Benign according to our data. Variant chr3-119500732-T-C is described in ClinVar as [Benign]. Clinvar id is 1617951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00974 (1483/152310) while in subpopulation SAS AF= 0.0309 (149/4822). AF 95% confidence interval is 0.0269. There are 12 homozygotes in gnomad4. There are 778 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMMDC1	NM_016589.4	c.232T>C	p.Cys78Arg	missense_variant	2/7	ENST00000494664.6
TIMMDC1	XM_017006556.2	c.194+1805T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMMDC1	ENST00000494664.6	c.232T>C	p.Cys78Arg	missense_variant	2/7	1	NM_016589.4	P1

Frequencies

GnomAD3 genomes AF: 0.00976 AC: 1486 AN: 152192 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.0117 AC: 2930 AN: 251228 Hom.: 27 AF XY: 0.0130 AC XY: 1770 AN XY: 135764

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00628

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0293

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0108 AC: 15720 AN: 1461750 Hom.: 138 Cov.: 31 AF XY: 0.0114 AC XY: 8286 AN XY: 727184

Gnomad4 AFR exome AF: 0.00469

Gnomad4 AMR exome AF: 0.00725

Gnomad4 ASJ exome AF: 0.00498

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0282

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.00993

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00974 AC: 1483 AN: 152310 Hom.: 12 Cov.: 33 AF XY: 0.0104 AC XY: 778 AN XY: 74478

Gnomad4 AFR AF: 0.00481

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0309

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0100 Hom.: 14

Bravo AF: 0.00852

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0106 AC: 91

ExAC AF: 0.0121 AC: 1475

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0130

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TIMMDC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	16
Dann	Benign	0.65
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.080
Sift	Benign	0.096	T
Sift4G	Benign	0.34	T
Polyphen		0.39	B
Vest4		0.11
MPC		0.46
ClinPred		0.0094	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149492706; hg19: chr3-119219579;