rs1131265

Variant names:

• chr3-119503609-G-C
• rs1131265
• NM_016589.4:c.438G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-119503609-G-C
• chr3-119503609-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016589.4(TIMMDC1):​c.438G>C​(p.Val146Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,606,236 control chromosomes in the GnomAD database, including 28,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2719 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26264 hom.)
• Consequence: TIMMDC1 NM_016589.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.599
• Publications: 43 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 complex I deficiency, nuclear type 31

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-119503609-G-C is Benign according to our data. Variant chr3-119503609-G-C is described in ClinVar as Benign. ClinVar VariationId is 1621743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.599 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 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.438G>C	p.Val146Val	synonymous	Exon 3 of 7	NP_057673.2
	TIMMDC1	NM_001438040.1		c.194+4682G>C		intron	N/A	NP_001424969.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMMDC1	ENST00000494664.6	TSL:1 MANE Select	c.438G>C	p.Val146Val	synonymous	Exon 3 of 7	ENSP00000418803.1
	TIMMDC1	ENST00000264244.7	TSL:1	n.438G>C		non_coding_transcript_exon	Exon 3 of 6	ENSP00000264244.3
	TIMMDC1	ENST00000854204.1		c.438G>C	p.Val146Val	synonymous	Exon 3 of 7	ENSP00000524263.1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28167 AN: 152084 Hom.: 2720 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.177 AC: 42943 AN: 242994 AF XY: 0.177

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.332

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.187 AC: 271409 AN: 1454034 Hom.: 26264 Cov.: 30 AF XY: 0.186 AC XY: 134458 AN XY: 723140

African (AFR) AF: 0.205 AC: 6824 AN: 33244

American (AMR) AF: 0.113 AC: 4940 AN: 43574

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 3878 AN: 25966

East Asian (EAS) AF: 0.319 AC: 12630 AN: 39574

South Asian (SAS) AF: 0.179 AC: 15231 AN: 84916

European-Finnish (FIN) AF: 0.123 AC: 6551 AN: 53124

Middle Eastern (MID) AF: 0.197 AC: 1131 AN: 5730

European-Non Finnish (NFE) AF: 0.188 AC: 208802 AN: 1107890

Other (OTH) AF: 0.190 AC: 11422 AN: 60016

GnomAD4 genome AF: 0.185 AC: 28174 AN: 152202 Hom.: 2719 Cov.: 32 AF XY: 0.181 AC XY: 13489 AN XY: 74412

African (AFR) AF: 0.201 AC: 8333 AN: 41508

American (AMR) AF: 0.136 AC: 2084 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3472

East Asian (EAS) AF: 0.330 AC: 1710 AN: 5180

South Asian (SAS) AF: 0.191 AC: 921 AN: 4830

European-Finnish (FIN) AF: 0.120 AC: 1269 AN: 10602

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12686 AN: 68006

Other (OTH) AF: 0.186 AC: 394 AN: 2116

Alfa AF: 0.183 Hom.: 861

Bravo AF: 0.186

Asia WGS AF: 0.241 AC: 836 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	TIMMDC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.60
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: rs1131265; hg19: chr3-119222456; COSMIC: COSV51786217;