chr1-235112077-T-C

Position:

• chr1-235112077-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014765.3(TOMM20):​c.425A>G​(p.Asp142Gly) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TOMM20 NM_014765.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

Genes affected

TOMM20 (HGNC:20947): (translocase of outer mitochondrial membrane 20) Enables protein-transporting ATPase activity and unfolded protein binding activity. Involved in protein targeting to mitochondrion. Located in mitochondria-associated endoplasmic reticulum membrane and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27445763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOMM20	NM_014765.3	c.425A>G	p.Asp142Gly	missense_variant	5/5	ENST00000366607.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOMM20	ENST00000366607.5	c.425A>G	p.Asp142Gly	missense_variant	5/5	1	NM_014765.3	P1
TOMM20	ENST00000467767.5	n.325A>G		non_coding_transcript_exon_variant	4/4	3
TOMM20	ENST00000473132.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.425A>G (p.D142G) alteration is located in exon 5 (coding exon 5) of the TOMM20 gene. This alteration results from a A to G substitution at nucleotide position 425, causing the aspartic acid (D) at amino acid position 142 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	0.0037	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.20
Sift	Benign	0.13	T
Sift4G	Benign	0.085	T
Polyphen		0.011	B
Vest4		0.53
MutPred		0.55		Loss of stability (P = 0.0166);
MVP		0.35
MPC		1.3
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.65
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-235275392;