NM_001128917.2:c.634G>C

Variant names:

• chr19-44894057-G-C
• rs748960699
• NM_001128917.2:c.634G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128917.2(TOMM40):​c.634G>C​(p.Val212Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000147 in 1,361,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V212M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TOMM40 NM_001128917.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16984278).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMM40	NM_001128917.2	MANE Select	c.634G>C	p.Val212Leu	missense	Exon 5 of 9	NP_001122389.1	O96008-1
	TOMM40	NM_001128916.2		c.634G>C	p.Val212Leu	missense	Exon 6 of 10	NP_001122388.1	O96008-1
	TOMM40	NM_006114.3		c.634G>C	p.Val212Leu	missense	Exon 6 of 10	NP_006105.1	O96008-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMM40	ENST00000426677.7	TSL:1 MANE Select	c.634G>C	p.Val212Leu	missense	Exon 5 of 9	ENSP00000410339.1	O96008-1
	TOMM40	ENST00000252487.9	TSL:1	c.634G>C	p.Val212Leu	missense	Exon 6 of 10	ENSP00000252487.4	O96008-1
	TOMM40	ENST00000405636.6	TSL:1	c.634G>C	p.Val212Leu	missense	Exon 6 of 10	ENSP00000385184.2	O96008-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1361352 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 666452

African (AFR) AF: 0.00 AC: 0 AN: 30144

American (AMR) AF: 0.00 AC: 0 AN: 30556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20112

East Asian (EAS) AF: 0.00 AC: 0 AN: 37740

South Asian (SAS) AF: 0.0000141 AC: 1 AN: 70804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4356

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061760

Other (OTH) AF: 0.00 AC: 0 AN: 55884

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.074
Sift	Benign	0.31	T
Sift4G	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.26		Loss of sheet (P = 0.0817)
MVP		0.068
MPC		0.95
ClinPred		0.33	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
Mutation Taster		=82/18	polymorphism

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: rs748960699; hg19: chr19-45397314;