9-137278768-C-A

Position:

• chr9-137278768-C-A

Variant summary

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

The NM_017723.3(TOR4A):​c.79C>A​(p.Arg27Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000782 in 1,278,602 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: 7.8e-7 (0 hom.)
• Consequence: TOR4A NM_017723.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05

Genes affected

TOR4A (HGNC:25981): (torsin family 4 member A) Predicted to enable ATP binding activity. Predicted to be located in extracellular region and platelet alpha granule lumen. Predicted to be active in endoplasmic reticulum lumen and nuclear envelope. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOR4A	NM_017723.3	c.79C>A	p.Arg27Ser	missense_variant	2/2	ENST00000357503.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOR4A	ENST00000357503.3	c.79C>A	p.Arg27Ser	missense_variant	2/2	2	NM_017723.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.82e-7 AC: 1 AN: 1278602 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 627650

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: 9.66e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 26, 2023

The c.79C>A (p.R27S) alteration is located in exon 2 (coding exon 1) of the TOR4A gene. This alteration results from a C to A substitution at nucleotide position 79, causing the arginine (R) at amino acid position 27 to be replaced by a serine (S). 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	0.59
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.97	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.073	T
Polyphen		0.99	D
Vest4		0.60
MutPred		0.59		Loss of methylation at R27 (P = 0.0217);
MVP		0.42
MPC		2.5
ClinPred		0.98	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-140173220;