Genetic Variant TOR1AIP1:p.Arg7Leu (chr1-179882522-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015602.4(TOR1AIP1):c.20G>T(p.Arg7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000765 in 1,306,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

TOR1AIP1
NM_015602.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.21

Publications

0 publications found

Variant links:

Genes affected

TOR1AIP1 (HGNC:29456): (torsin 1A interacting protein 1) This gene encodes a type 2 integral membrane protein that binds A- and B-type lamins. The encoded protein localizes to the inner nuclear membrane and may be involved in maintaining the attachment of the nuclear membrane to the nuclear lamina during cell division. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2016]

TOR1AIP1 links:

TOR1AIP2 (HGNC:24055): (torsin 1A interacting protein 2) One of the two protein isoforms encoded by this gene is a type II integral membrane protein found in the endoplasmic reticulum (ER). The encoded protein is a cofactor for the ATPase TorsinA, regulating the amount of TorsinA present in the ER compared to that found in the nuclear envelope. Defects in this protein are a cause of early onset primary dystonia, a neuromuscular disease. The other isoform encoded by this gene is an interferon alpha responsive protein whose cellular role has yet to be determined. [provided by RefSeq, Mar 2017]

TOR1AIP2 links:

ENSG00000272906 (HGNC:):

ENSG00000272906 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16029891).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015602.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOR1AIP1	NM_015602.4	MANE Select	c.20G>T	p.Arg7Leu	missense	Exon 1 of 10	NP_056417.2
TOR1AIP1	NM_001267578.2		c.20G>T	p.Arg7Leu	missense	Exon 1 of 10	NP_001254507.1	Q5JTV8-3
LOC139427322	NM_001436163.1		c.*129G>T		downstream_gene	N/A	NP_001423092.1	A0AAQ5BH39

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOR1AIP1	ENST00000606911.7	TSL:1 MANE Select	c.20G>T	p.Arg7Leu	missense	Exon 1 of 10	ENSP00000476687.1	Q5JTV8-1
TOR1AIP1	ENST00000271583.7	TSL:5	c.20G>T	p.Arg7Leu	missense	Exon 1 of 11	ENSP00000271583.3	J3KN66
TOR1AIP1	ENST00000528443.6	TSL:2	c.20G>T	p.Arg7Leu	missense	Exon 1 of 10	ENSP00000435365.2	Q5JTV8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.65e-7

AC:

AN:

1306496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

634944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28414

American (AMR)

AF:

0.00

AC:

AN:

19964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18828

East Asian (EAS)

AF:

0.00

AC:

AN:

34666

South Asian (SAS)

AF:

0.0000158

AC:

AN:

63304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5032

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1037516

Other (OTH)

AF:

0.00

AC:

AN:

53892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.75

M_CAP

Benign

0.019

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

1.2

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.0

REVEL

Benign

0.026

Sift

Benign

0.22

Sift4G

Uncertain

0.030

Polyphen

0.015

Vest4

0.20

MutPred

0.39

Loss of disorder (P = 0.007)

MVP

0.43

MPC

0.57

ClinPred

0.58

GERP RS

2.4

PromoterAI

-0.030

Neutral

(source)

Varity_R

0.073

gMVP

0.23

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over