19-44892457-T-C

Variant names:

• chr19-44892457-T-C
• rs157581
• NM_001128917.2:c.339T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001128917.2(TOMM40):​c.339T>C​(p.Phe113Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,611,534 control chromosomes in the GnomAD database, including 46,154 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 0.29 (7174 hom., cov: 31)
  • Exomes 𝑓: 0.23 (38980 hom.)
• Consequence: TOMM40 NM_001128917.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40
• Publications: 79 publications found

Genes affected

TOMM40 (HGNC:18001): (translocase of outer mitochondrial membrane 40) The protein encoded by this gene is localized in the outer membrane of the mitochondria. It is the channel-forming subunit of the translocase of the mitochondrial outer membrane (TOM) complex that is essential for import of protein precursors into mitochondria. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2015]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP7: Synonymous conserved (PhyloP=2.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128917.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMM40	NM_001128917.2	MANE Select	c.339T>C	p.Phe113Phe	synonymous	Exon 2 of 9	NP_001122389.1
	TOMM40	NM_001128916.2		c.339T>C	p.Phe113Phe	synonymous	Exon 3 of 10	NP_001122388.1
	TOMM40	NM_006114.3		c.339T>C	p.Phe113Phe	synonymous	Exon 3 of 10	NP_006105.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMM40	ENST00000426677.7	TSL:1 MANE Select	c.339T>C	p.Phe113Phe	synonymous	Exon 2 of 9	ENSP00000410339.1
	TOMM40	ENST00000252487.9	TSL:1	c.339T>C	p.Phe113Phe	synonymous	Exon 3 of 10	ENSP00000252487.4
	TOMM40	ENST00000405636.6	TSL:1	c.339T>C	p.Phe113Phe	synonymous	Exon 3 of 10	ENSP00000385184.2

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43614 AN: 151764 Hom.: 7146 Cov.: 31

Gnomad AFR AF: 0.458

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.225

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.241

GnomAD2 exomes AF: 0.246 AC: 61815 AN: 251406 AF XY: 0.237

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.228

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.227 AC: 331325 AN: 1459652 Hom.: 38980 Cov.: 33 AF XY: 0.225 AC XY: 163564 AN XY: 726170

African (AFR) AF: 0.472 AC: 15775 AN: 33400

American (AMR) AF: 0.281 AC: 12573 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 5782 AN: 26134

East Asian (EAS) AF: 0.262 AC: 10402 AN: 39696

South Asian (SAS) AF: 0.210 AC: 18058 AN: 86168

European-Finnish (FIN) AF: 0.231 AC: 12361 AN: 53412

Middle Eastern (MID) AF: 0.158 AC: 700 AN: 4440

European-Non Finnish (NFE) AF: 0.218 AC: 241949 AN: 1111456

Other (OTH) AF: 0.228 AC: 13725 AN: 60222

GnomAD4 genome AF: 0.288 AC: 43704 AN: 151882 Hom.: 7174 Cov.: 31 AF XY: 0.289 AC XY: 21480 AN XY: 74228

African (AFR) AF: 0.458 AC: 18939 AN: 41354

American (AMR) AF: 0.267 AC: 4077 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3470

East Asian (EAS) AF: 0.247 AC: 1278 AN: 5166

South Asian (SAS) AF: 0.223 AC: 1072 AN: 4812

European-Finnish (FIN) AF: 0.225 AC: 2378 AN: 10568

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14516 AN: 67938

Other (OTH) AF: 0.248 AC: 523 AN: 2110

Alfa AF: 0.244 Hom.: 8681

Bravo AF: 0.297

Asia WGS AF: 0.334 AC: 1162 AN: 3478

EpiCase AF: 0.206

EpiControl AF: 0.200

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		2.4
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs157581; hg19: chr19-45395714; COSMIC: COSV52976179; COSMIC: COSV52976179;