17-998796-G-A

Variant names:

• chr17-998796-G-A
• rs879394345
• NM_013337.4:c.256G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_013337.4(TIMM22):​c.256G>A​(p.Ala86Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TIMM22 NM_013337.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.49

Genes affected

TIMM22 (HGNC:17317): (translocase of inner mitochondrial membrane 22) Multipass transmembrane proteins are brought into mitochondria and inserted into the mitochondrial inner membrane by way of the TIM22 complex. This complex has six subunits and is a twin-pore translocase. The protein encoded by this gene is a subunit of TIM22 and represents the voltage-activated and signal-gated channel. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM22	NM_013337.4	c.256G>A	p.Ala86Thr	missense_variant	Exon 2 of 4	ENST00000327158.5	NP_037469.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM22	ENST00000327158.5	c.256G>A	p.Ala86Thr	missense_variant	Exon 2 of 4	1	NM_013337.4	ENSP00000320236.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461446 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.256G>A (p.A86T) alteration is located in exon 2 (coding exon 2) of the TIMM22 gene. This alteration results from a G to A substitution at nucleotide position 256, causing the alanine (A) at amino acid position 86 to be replaced by a threonine (T). 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	0.31
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.58		Gain of glycosylation at A86 (P = 0.1062);
MVP		0.42
MPC		0.57
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs879394345; hg19: chr17-902036;