3-119500726-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016589.4(TIMMDC1):c.226A>G(p.Asn76Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0501 in 1,613,510 control chromosomes in the GnomAD database, including 9,567 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (4497 hom., cov: 32)
  • Exomes 𝑓: 0.040 (5070 hom.)
• Consequence: TIMMDC1 NM_016589.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0380

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=4.7191978E-4).
• BP6: Variant 3-119500726-A-G is Benign according to our data. Variant chr3-119500726-A-G is described in ClinVar as [Benign]. Clinvar id is 1542422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMMDC1	NM_016589.4	c.226A>G	p.Asn76Asp	missense_variant	2/7	ENST00000494664.6
TIMMDC1	XM_017006556.2	c.194+1799A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMMDC1	ENST00000494664.6	c.226A>G	p.Asn76Asp	missense_variant	2/7	1	NM_016589.4	P1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22806 AN: 152030 Hom.: 4479 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0727

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0136

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.134

GnomAD3 exomes AF: 0.0638 AC: 15996 AN: 250564 Hom.: 2128 AF XY: 0.0590 AC XY: 7989 AN XY: 135400

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.0375

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.0114

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0249

Gnomad OTH exome AF: 0.0453

GnomAD4 exome AF: 0.0397 AC: 57964 AN: 1461362 Hom.: 5070 Cov.: 31 AF XY: 0.0404 AC XY: 29391 AN XY: 726956

Gnomad4 AFR exome AF: 0.479

Gnomad4 AMR exome AF: 0.0408

Gnomad4 ASJ exome AF: 0.0218

Gnomad4 EAS exome AF: 0.00998

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0606

GnomAD4 genome AF: 0.150 AC: 22866 AN: 152148 Hom.: 4497 Cov.: 32 AF XY: 0.146 AC XY: 10872 AN XY: 74404

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.0726

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0137

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.133

Alfa AF: 0.0491 Hom.: 1848

Bravo AF: 0.167

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.449 AC: 1980

ESP6500EA AF: 0.0264 AC: 227

ExAC AF: 0.0735 AC: 8925

Asia WGS AF: 0.126 AC: 441 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0250

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 06, 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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.0
Dann	Benign	0.57
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.00047	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.61	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.041
Sift	Benign	0.80	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.035
MPC		0.18
ClinPred		0.0013	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.62

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: rs11539377; hg19: chr3-119219573; COSMIC: COSV51787767; COSMIC: COSV51787767;