7-22822707-A-G

Position:

• chr7-22822707-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_019059.5(TOMM7):​c.73T>C​(p.Trp25Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOMM7 NM_019059.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 8.07

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 7-22822707-A-G is Pathogenic according to our data. Variant chr7-22822707-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1679423.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOMM7	NM_019059.5	c.73T>C	p.Trp25Arg	missense_variant	1/3	ENST00000358435.9	NP_061932.1
TOMM7	NR_168014.1	n.129+14T>C		intron_variant
TOMM7	NR_168015.1	n.129+14T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOMM7	ENST00000358435.9	c.73T>C	p.Trp25Arg	missense_variant	1/3	1	NM_019059.5	ENSP00000351214.4
TOMM7	ENST00000496129.1	n.104T>C		non_coding_transcript_exon_variant	1/2	1
TOMM7	ENST00000372879.8	c.73T>C	p.Trp25Arg	missense_variant	1/4	4		ENSP00000361970.4
TOMM7	ENST00000463284.2	n.143T>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

See cases Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Apr 28, 2022

The Trp25Arg variant in TOMM7 likely creates a hypomorphic allele supported by mouse studies. The variant is absent in public databases and prediction tools indicates high pathogenicity. -

Garg-Mishra progeroid syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.85	T
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-9.4	D;D;.
REVEL	Pathogenic	0.79
Sift	Benign	0.050	D;D;.
Sift4G	Benign	0.076	T;D;T
Polyphen		0.0060	B;.;.
Vest4		0.93
MutPred		0.84		Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);Gain of solvent accessibility (P = 0.0584);
MVP		0.18
MPC		0.25
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.91
gMVP		0.71

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-22862326;