10-46003286-A-G

Variant names:

• chr10-46003286-A-G
• rs369863871
• NM_006327.4:c.598A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006327.4(TIMM23):​c.598A>G​(p.Met200Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIMM23 NM_006327.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

Genes affected

TIMM23 (HGNC:17312): (translocase of inner mitochondrial membrane 23) The protein encoded by this gene is part of a complex located in the inner mitochondrial membrane that mediates the transport of transit peptide-containing proteins across the membrane. Multiple transcript variants, one protein-coding and others not protein-coding, have been found for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1990861).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM23	NM_006327.4	c.598A>G	p.Met200Val	missense_variant	Exon 7 of 7	ENST00000580018.4	NP_006318.1
TIMM23	NR_073029.2	n.858A>G		non_coding_transcript_exon_variant	Exon 8 of 8
TIMM23	NR_073030.2	n.675A>G		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM23	ENST00000580018.4	c.598A>G	p.Met200Val	missense_variant	Exon 7 of 7	1	NM_006327.4	ENSP00000464522.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.598A>G (p.M200V) alteration is located in exon 7 (coding exon 7) of the TIMM23 gene. This alteration results from a A to G substitution at nucleotide position 598, causing the methionine (M) at amino acid position 200 to be replaced by a valine (V). 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	Benign	0.071
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.62
DEOGEN2	Benign	0.17	T
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.20	T
Sift4G	Benign	0.13	T
Vest4		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs369863871; hg19: chr10-51592536;