rs373049289

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_015602.4(TOR1AIP1):c.452T>C(p.Leu151Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L151V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TOR1AIP1
NM_015602.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.64

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 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy type 2Y
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

TOR1AIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10560739).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000125 (19/152200) while in subpopulation AFR AF = 0.00041 (17/41452). AF 95% confidence interval is 0.000261. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4 link	c.452T>C	p.Leu151Pro	missense_variant	Exon 1 of 10	ENST00000606911.7	NP_056417.2	Q5JTV8-1
TOR1AIP1	NM_001267578.2 link	c.452T>C	p.Leu151Pro	missense_variant	Exon 1 of 10		NP_001254507.1	Q5JTV8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7 link	c.452T>C	p.Leu151Pro	missense_variant	Exon 1 of 10	1	NM_015602.4	ENSP00000476687.1		Q5JTV8-1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000450

AC:

AN:

244556

AF XY:

0.0000374

show subpopulations

Gnomad AFR exome

AF:

0.000748

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460840

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726710

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111724

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

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

AF:

0.000125

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.000410

AC:

AN:

41452

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000685

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2Y

Uncertain:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 151 of the TOR1AIP1 protein (p.Leu151Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TOR1AIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 581557). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TOR1AIP1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Dec 17, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

.;.;T;.;T

Eigen

Benign

-0.094

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.84

T;D;T;T;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.7

M;.;M;.;.

PhyloP100

1.6

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.7

D;D;.;.;D

REVEL

Benign

0.17

Sift

Uncertain

0.0020

D;D;.;.;D

Sift4G

Uncertain

0.0060

D;D;T;T;D

Polyphen

1.0

.;.;D;.;.

Vest4

0.39

MVP

0.56

MPC

0.61

ClinPred

0.20

GERP RS

3.2

PromoterAI

0.061

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.49

gMVP

0.085

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over