Genetic Variant NM_012192.4:c.29A>C (chr11-6481545-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_012192.4(TIMM10B):c.29A>C(p.Gln10Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,458,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TIMM10B
NM_012192.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54

Variant links:

Genes affected

TIMM10B (HGNC:4022): (translocase of inner mitochondrial membrane 10B) FXC1, or TIMM10B, belongs to a family of evolutionarily conserved proteins that are organized in heterooligomeric complexes in the mitochondrial intermembrane space. These proteins mediate the import and insertion of hydrophobic membrane proteins into the mitochondrial inner membrane.[supplied by OMIM, Apr 2004]

TIMM10B links:

ENSG00000283977 (HGNC:):

ENSG00000283977 links:

ARFIP2 (HGNC:17160): (ADP ribosylation factor interacting protein 2) Enables several functions, including GTP-dependent protein binding activity; membrane curvature sensor activity; and phosphatidylinositol-4-phosphate binding activity. Involved in actin cytoskeleton organization. Located in cell cortex; ruffle; and trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARFIP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
TIMM10B	NM_012192.4 link	c.29A>C	p.Gln10Pro	missense_variant	Exon 1 of 3	ENST00000254616.11	NP_036324.1	Q9Y5J6B2R4A9
ARFIP2	NM_001376558.2 link	c.-357T>G		upstream_gene_variant		ENST00000396777.8	NP_001363487.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TIMM10B	ENST00000254616.11 link	c.29A>C	p.Gln10Pro	missense_variant	Exon 1 of 3	1	NM_012192.4	ENSP00000254616.6	Q9Y5J6
ENSG00000283977	ENST00000640959.1 link	n.29A>C		non_coding_transcript_exon_variant	Exon 1 of 5	4		ENSP00000491841.1
ARFIP2	ENST00000396777.8 link	c.-357T>G		upstream_gene_variant		2	NM_001376558.2	ENSP00000379998.3	P53365-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000249

AC:

AN:

240514

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

130128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000178

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000549

AC:

AN:

1458518

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725140

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.29A>C (p.Q10P) alteration is located in exon 1 (coding exon 1) of the TIMM10B gene. This alteration results from a A to C substitution at nucleotide position 29, causing the glutamine (Q) at amino acid position 10 to be replaced by a proline (P). 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

0.25

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

1.9

L;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.5

D;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.010

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.91

P;.

Vest4

0.55

MutPred

0.71

Gain of glycosylation at Q10 (P = 0.0347);Gain of glycosylation at Q10 (P = 0.0347);

MVP

0.72

MPC

0.44

ClinPred

0.78

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.97

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over