22-20036808-A-T

Position:

• chr22-20036808-A-T

Variant summary

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

The NM_152906.7(TANGO2):​c.10A>T​(p.Ile4Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TANGO2 NM_152906.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

Genes affected

TANGO2 (HGNC:25439): (transport and golgi organization 2 homolog) This gene belongs to the transport and Golgi organization family, whose members are predicted to play roles in secretory protein loading in the endoplasmic reticulum. Depletion of this gene in Drosophila S2 cells causes fusion of the Golgi with the ER. In mouse tissue culture cells, this protein co-localizes with a mitochondrially targeted mCherry protein and displays very low levels of co-localization with Golgi and peroxisomes. Allelic variants of this gene are associated with rhabdomyolysis, metabolic crises with encephalopathy, and cardiac arrhythmia. [provided by RefSeq, Apr 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, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TANGO2	NM_152906.7	c.10A>T	p.Ile4Phe	missense_variant	2/9	ENST00000327374.9	NP_690870.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TANGO2	ENST00000327374.9	c.10A>T	p.Ile4Phe	missense_variant	2/9	1	NM_152906.7	ENSP00000332721	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2024

The c.10A>T (p.I4F) alteration is located in exon 2 (coding exon 1) of the TANGO2 gene. This alteration results from a A to T substitution at nucleotide position 10, causing the isoleucine (I) at amino acid position 4 to be replaced by a phenylalanine (F). 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	0.73
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	.;T;T;T;.;.;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.7	H;.;.;.;H;.;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D;D;D;.;D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0040	D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;.;D;.
Vest4		0.83
MutPred		0.72		Loss of ubiquitination at K7 (P = 0.1055);Loss of ubiquitination at K7 (P = 0.1055);Loss of ubiquitination at K7 (P = 0.1055);Loss of ubiquitination at K7 (P = 0.1055);Loss of ubiquitination at K7 (P = 0.1055);Loss of ubiquitination at K7 (P = 0.1055);Loss of ubiquitination at K7 (P = 0.1055);Loss of ubiquitination at K7 (P = 0.1055);
MVP		0.15
MPC		0.67
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1212736790; hg19: chr22-20024331;