7-22813187-T-C

Position:

• chr7-22813187-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMM7	NM_019059.5	c.153-2A>G		splice_acceptor_variant, intron_variant		ENST00000358435.9	NP_061932.1
TOMM7	NR_168014.1	n.179-2A>G		splice_acceptor_variant, intron_variant
TOMM7	NR_168015.1	n.130-2A>G		splice_acceptor_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMM7	ENST00000358435.9	c.153-2A>G		splice_acceptor_variant, intron_variant		1	NM_019059.5	ENSP00000351214.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TOMM7-related early onset Leigh disease Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

-

A novel homozygous splice site variant, NC_000007.14:g.22813187T>C (NM_019059.5:c.153-2A>C) in intron 2 of TOMM7 was observed in a homozygous state in proband. On segregation analysis, this variant was found to be in heterozygous state in her parents. This variant is not present in the gnomAD (v4.1.0) population database and our in-house database of 3343 exomes. Biallelic disease-causing variants in TOMM7 are known to cause Garg-Mishra progeroid syndrome (MIM# 620601). To date, two individuals from two unrelated families have been reported with short stature, lipodystrophy, progeria, developmental delay, hypotonia, and skeletal dysplasia (Garg et.al. 2022; Young et al. 2023). Notably, the clinical features observed in proband are of severe and early-onset, with neurologic and metabolic features suggestive of mitochondrial dysfunction and neuro imaging findings indicative of Leigh disease (Yeole et al. 2024). Thus, the above-mentioned variant in the homozygous state is interpreted to be the likely cause for the early-onset mitochondrial dysfunction observed in proband. -

Computational scores

Source: dbNSFP v4.3

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
GERP RS		5.8

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-22852806;