chr7-22813187-T-C

Variant names:

• chr7-22813187-T-C
• NM_019059.5:c.153-2A>G

Variant summary

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

The NM_019059.5(TOMM7):​c.153-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOMM7 NM_019059.5 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00
• Publications: 0 publications found

Genes affected

TOMM7 (HGNC:21648): (translocase of outer mitochondrial membrane 7) This gene encodes a subunit of the translocase of the outer mitochondrial membrane. The encoded protein regulates the assembly and stability of the translocase complex. [provided by RefSeq, Oct 2012]

TOMM7 Gene-Disease associations (from GenCC):

• Garg-Mishra progeroid syndrome

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019059.5. 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
	TOMM7	NM_019059.5	MANE Select	c.153-2A>G		splice_acceptor intron	N/A	NP_061932.1	Q9P0U1
	TOMM7	NR_168014.1		n.179-2A>G		splice_acceptor intron	N/A
	TOMM7	NR_168015.1		n.130-2A>G		splice_acceptor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOMM7	ENST00000358435.9	TSL:1 MANE Select	c.153-2A>G		splice_acceptor intron	N/A	ENSP00000351214.4	Q9P0U1
	TOMM7	ENST00000483581.1	TSL:1	n.337-2A>G		splice_acceptor intron	N/A
	TOMM7	ENST00000372879.8	TSL:4	c.290-2A>G		splice_acceptor intron	N/A	ENSP00000361970.4	A6NIV2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	TOMM7-related early onset Leigh disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		4.0
GERP RS		5.8
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: -20
DS_AL_spliceai		0.92		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr7-22852806;