3-119508400-G-A

Variant names:

• chr3-119508400-G-A
• rs4688011
• NM_016589.4:c.517+4379G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016589.4(TIMMDC1):​c.517+4379G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,206 control chromosomes in the GnomAD database, including 2,339 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (2339 hom., cov: 33)
• Consequence: TIMMDC1 NM_016589.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.599
• Publications: 25 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: PanelApp Australia, 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

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.517+4379G>A		intron	N/A	NP_057673.2	Q9NPL8
	TIMMDC1	NM_001438040.1		c.195-8805G>A		intron	N/A	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.517+4379G>A		intron	N/A	ENSP00000418803.1	Q9NPL8
	TIMMDC1	ENST00000264244.7	TSL:1	n.517+4379G>A		intron	N/A	ENSP00000264244.3	G3XA94
	TIMMDC1	ENST00000854204.1		c.517+4379G>A		intron	N/A	ENSP00000524263.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23422 AN: 152088 Hom.: 2337 Cov.: 33

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.167

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.154 AC: 23429 AN: 152206 Hom.: 2339 Cov.: 33 AF XY: 0.158 AC XY: 11782 AN XY: 74392

African (AFR) AF: 0.0355 AC: 1474 AN: 41558

American (AMR) AF: 0.180 AC: 2759 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 810 AN: 3468

East Asian (EAS) AF: 0.276 AC: 1430 AN: 5182

South Asian (SAS) AF: 0.175 AC: 844 AN: 4828

European-Finnish (FIN) AF: 0.253 AC: 2673 AN: 10562

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12718 AN: 67992

Other (OTH) AF: 0.167 AC: 353 AN: 2114

Alfa AF: 0.167 Hom.: 3361

Bravo AF: 0.146

Asia WGS AF: 0.201 AC: 700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.52
PhyloP100		-0.60
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4688011; hg19: chr3-119227247;