3-119498942-G-T

Variant names:

• chr3-119498942-G-T
• rs200200314
• NM_016589.4:c.194+15G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_016589.4(TIMMDC1):​c.194+15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,613,194 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (18 hom.)
• Consequence: TIMMDC1 NM_016589.4 intron
• Scores: Splicing: ADA: 0.0006994
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.70
• Publications: 1 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-119498942-G-T is Benign according to our data. Variant chr3-119498942-G-T is described in ClinVar as Benign. ClinVar VariationId is 1592296.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00343 (522/152298) while in subpopulation NFE AF = 0.00529 (360/68026). AF 95% confidence interval is 0.00484. There are 0 homozygotes in GnomAd4. There are 247 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

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.194+15G>T		intron	N/A	NP_057673.2	Q9NPL8
	TIMMDC1	NM_001438040.1		c.194+15G>T		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.194+15G>T		intron	N/A	ENSP00000418803.1	Q9NPL8
	TIMMDC1	ENST00000264244.7	TSL:1	n.194+15G>T		intron	N/A	ENSP00000264244.3	G3XA94
	TIMMDC1	ENST00000854204.1		c.194+15G>T		intron	N/A	ENSP00000524263.1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 522 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00327 AC: 816 AN: 249472 AF XY: 0.00321

Gnomad AFR exome AF: 0.000644

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00560

Gnomad NFE exome AF: 0.00523

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00440 AC: 6426 AN: 1460896 Hom.: 18 Cov.: 31 AF XY: 0.00433 AC XY: 3149 AN XY: 726666

African (AFR) AF: 0.000718 AC: 24 AN: 33440

American (AMR) AF: 0.00139 AC: 62 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000580 AC: 50 AN: 86236

European-Finnish (FIN) AF: 0.00506 AC: 270 AN: 53376

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.00524 AC: 5818 AN: 1111274

Other (OTH) AF: 0.00320 AC: 193 AN: 60332

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.00332 AC XY: 247 AN XY: 74472

African (AFR) AF: 0.000722 AC: 30 AN: 41564

American (AMR) AF: 0.00438 AC: 67 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00529 AC: 360 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00273 Hom.: 0

Bravo AF: 0.00312

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	14
DANN	Benign	0.55
PhyloP100		2.7
PromoterAI		-0.020	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00070
SpliceAI score (max)		0.090		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: rs200200314; hg19: chr3-119217789;