NM_001128917.2:c.276G>T

Variant names:

• chr19-44892394-G-T
• rs146640981
• NM_001128917.2:c.276G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128917.2(TOMM40):​c.276G>T​(p.Glu92Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: TOMM40 NM_001128917.2 missense, splice_region
• Scores: Splicing: ADA: 0.00008399
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.636

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09468898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOMM40	NM_001128917.2	c.276G>T	p.Glu92Asp	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000426677.7	NP_001122389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOMM40	ENST00000426677.7	c.276G>T	p.Glu92Asp	missense_variant, splice_region_variant	Exon 2 of 9	1	NM_001128917.2	ENSP00000410339.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74300

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.045	T;T;.;T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.78	T;.;T;.;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.095	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	1.0	N;N;.;N;.
REVEL	Benign	0.070
Sift	Benign	1.0	T;T;.;T;.
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0080	B;B;B;B;.
Vest4		0.32
MutPred		0.50		Loss of ubiquitination at K89 (P = 0.1343);Loss of ubiquitination at K89 (P = 0.1343);Loss of ubiquitination at K89 (P = 0.1343);Loss of ubiquitination at K89 (P = 0.1343);Loss of ubiquitination at K89 (P = 0.1343);
MVP		0.11
MPC		0.051
ClinPred		0.24	T
GERP RS		1.2
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000084
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.070		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: rs146640981; hg19: chr19-45395651;