1-179889309-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PVS1_ModerateBP6BA1

The NM_001267578.2(TOR1AIP1):c.554-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.624 in 1,582,776 control chromosomes in the GnomAD database, including 311,571 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.60 ( 27524 hom., cov: 32)

Exomes 𝑓: 0.63 ( 284047 hom. )

Consequence

TOR1AIP1
NM_001267578.2 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 4.24

Publications

32 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):

TOR1AIP1-related multisystem disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
TOR1AIP1-related myopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2Y
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

TOR1AIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.034188036 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.8, offset of 3, new splice context is: ttctcttcctatattaacAGtga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 1-179889309-G-A is Benign according to our data. Variant chr1-179889309-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257701.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267578.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1AIP1	NM_015602.4	MANE Select	c.554-4G>A		splice_region intron	N/A	NP_056417.2
	TOR1AIP1	NM_001267578.2		c.554-1G>A		splice_acceptor intron	N/A	NP_001254507.1	Q5JTV8-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TOR1AIP1	ENST00000606911.7	TSL:1 MANE Select	c.554-4G>A	splice_region intron	N/A	ENSP00000476687.1	Q5JTV8-1
TOR1AIP1	ENST00000435319.8	TSL:1	c.191-4G>A	splice_region intron	N/A	ENSP00000393292.3	Q5JTV8-4
TOR1AIP1	ENST00000271583.7	TSL:5	c.554-1G>A	splice_acceptor intron	N/A	ENSP00000271583.3	J3KN66

Frequencies

GnomAD3 genomes

AF:

0.597

AC:

90703

AN:

151850

Hom.:

27499

Cov.:

show subpopulations

Gnomad AFR

AF:

0.495

Gnomad AMI

AF:

0.631

Gnomad AMR

AF:

0.682

Gnomad ASJ

AF:

0.663

Gnomad EAS

AF:

0.758

Gnomad SAS

AF:

0.689

Gnomad FIN

AF:

0.558

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.623

Gnomad OTH

AF:

0.624

GnomAD2 exomes

AF:

0.651

AC:

163002

AN:

250292

AF XY:

0.651

show subpopulations

Gnomad AFR exome

AF:

0.494

Gnomad AMR exome

AF:

0.768

Gnomad ASJ exome

AF:

0.664

Gnomad EAS exome

AF:

0.760

Gnomad FIN exome

AF:

0.562

Gnomad NFE exome

AF:

0.628

Gnomad OTH exome

AF:

0.649

GnomAD4 exome

AF:

0.627

AC:

896964

AN:

1430808

Hom.:

284047

Cov.:

AF XY:

0.629

AC XY:

448446

AN XY:

712786

show subpopulations

African (AFR)

AF:

0.492

AC:

16252

AN:

33026

American (AMR)

AF:

0.762

AC:

33821

AN:

44358

Ashkenazi Jewish (ASJ)

AF:

0.658

AC:

16857

AN:

25604

East Asian (EAS)

AF:

0.753

AC:

29701

AN:

39438

South Asian (SAS)

AF:

0.686

AC:

57526

AN:

83884

European-Finnish (FIN)

AF:

0.560

AC:

29490

AN:

52658

Middle Eastern (MID)

AF:

0.673

AC:

3814

AN:

5668

European-Non Finnish (NFE)

AF:

0.618

AC:

672095

AN:

1087102

Other (OTH)

AF:

0.633

AC:

37408

AN:

59070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

13578

27156

40733

54311

67889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18038

36076

54114

72152

90190

<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:

0.597

AC:

90767

AN:

151968

Hom.:

27524

Cov.:

AF XY:

0.597

AC XY:

44339

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.495

AC:

20488

AN:

41394

American (AMR)

AF:

0.682

AC:

10420

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.663

AC:

2303

AN:

3472

East Asian (EAS)

AF:

0.757

AC:

3925

AN:

5184

South Asian (SAS)

AF:

0.688

AC:

3321

AN:

4824

European-Finnish (FIN)

AF:

0.558

AC:

5874

AN:

10518

Middle Eastern (MID)

AF:

0.690

AC:

203

AN:

294

European-Non Finnish (NFE)

AF:

0.623

AC:

42331

AN:

67976

Other (OTH)

AF:

0.628

AC:

1328

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1867

3735

5602

7470

9337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

772

1544

2316

3088

3860

<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:

0.617

Hom.:

65714

Bravo

AF:

0.604

TwinsUK

AF:

0.619

AC:

2294

ALSPAC

AF:

0.608

AC:

2343

ESP6500AA

AF:

0.504

AC:

2219

ESP6500EA

AF:

0.624

AC:

5362

ExAC

AF:

0.646

AC:

78470

Asia WGS

AF:

0.705

AC:

2449

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive limb-girdle muscular dystrophy type 2Y (3)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.81

PhyloP100

4.2

GERP RS

5.3

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over