rs146976883

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015602.4(TOR1AIP1):c.70C>G(p.Pro24Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,517,228 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0030 ( 11 hom. )

Consequence

TOR1AIP1
NM_015602.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.27

Publications

3 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:

ENSG00000272906 (HGNC:):

ENSG00000272906 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007002741).

BP6

Variant 1-179882572-C-G is Benign according to our data. Variant chr1-179882572-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476288.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00223 (340/152210) while in subpopulation NFE AF = 0.00348 (237/68006). AF 95% confidence interval is 0.00312. There are 3 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4 link	c.70C>G	p.Pro24Ala	missense_variant	Exon 1 of 10	ENST00000606911.7	NP_056417.2	Q5JTV8-1
TOR1AIP1	NM_001267578.2 link	c.70C>G	p.Pro24Ala	missense_variant	Exon 1 of 10		NP_001254507.1	Q5JTV8-3
LOC139427322	NM_001436163.1 link	c.*179C>G		downstream_gene_variant			NP_001423092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7 link	c.70C>G	p.Pro24Ala	missense_variant	Exon 1 of 10	1	NM_015602.4	ENSP00000476687.1		Q5JTV8-1
ENSG00000293564	ENST00000713864.1 link	c.*179C>G		downstream_gene_variant				ENSP00000519169.1

Frequencies

GnomAD3 genomes

AF:

0.00224

AC:

340

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00509

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00348

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00220

AC:

353

AN:

160708

AF XY:

0.00218

show subpopulations

Gnomad AFR exome

AF:

0.000537

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00362

Gnomad NFE exome

AF:

0.00331

Gnomad OTH exome

AF:

0.00272

GnomAD4 exome

AF:

0.00300

AC:

4089

AN:

1365018

Hom.:

Cov.:

AF XY:

0.00298

AC XY:

1995

AN XY:

669738

show subpopulations

African (AFR)

AF:

0.000465

AC:

AN:

30126

American (AMR)

AF:

0.000779

AC:

AN:

28256

Ashkenazi Jewish (ASJ)

AF:

0.00324

AC:

AN:

19756

East Asian (EAS)

AF:

0.00

AC:

AN:

38644

South Asian (SAS)

AF:

0.000400

AC:

AN:

70006

European-Finnish (FIN)

AF:

0.00324

AC:

157

AN:

48502

Middle Eastern (MID)

AF:

0.000389

AC:

AN:

5142

European-Non Finnish (NFE)

AF:

0.00342

AC:

3659

AN:

1068470

Other (OTH)

AF:

0.00255

AC:

143

AN:

56116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

248

496

745

993

1241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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:

0.00223

AC:

340

AN:

152210

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41540

American (AMR)

AF:

0.000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00509

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00348

AC:

237

AN:

68006

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00371

Hom.:

Bravo

AF:

0.00194

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.00211

AC:

249

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ENSG00000272906: BS2; TOR1AIP1: BS2 -

May 06, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2Y

Benign:3

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Apr 08, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.70C>G (p.P24A) alteration is located in exon 1 (coding exon 1) of the TOR1AIP1 gene. This alteration results from a C to G substitution at nucleotide position 70, causing the proline (P) at amino acid position 24 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

TOR1AIP1-related disorder

Benign:1

Apr 01, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.0070

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

2.0

M;.;M

PhyloP100

3.3

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.1

D;D;.

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.56

MVP

0.72

MPC

0.51

ClinPred

0.034

GERP RS

5.3

PromoterAI

0.17

Neutral

(source)

Varity_R

0.47

gMVP

0.17

Mutation Taster

=84/16

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