9-137278900-C-A

Position:

• chr9-137278900-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017723.3(TOR4A):​c.211C>A​(p.Leu71Met) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TOR4A NM_017723.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.342

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060247004).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR4A	NM_017723.3	c.211C>A	p.Leu71Met	missense_variant	2/2	ENST00000357503.3	NP_060193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR4A	ENST00000357503.3	c.211C>A	p.Leu71Met	missense_variant	2/2	2	NM_017723.3	ENSP00000350102.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1421760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 705608

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: 0.00

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

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.211C>A (p.L71M) 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 211, causing the leucine (L) at amino acid position 71 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.8
DANN	Benign	0.89
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	M
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.030
Sift	Benign	0.15	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.16		Gain of methylation at R68 (P = 0.2136);
MVP		0.13
MPC		1.5
ClinPred		0.047	T
GERP RS		0.77
Varity_R		0.069
gMVP		0.18

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: rs1332328803; hg19: chr9-140173352;