rs2245425

Variant names:

• chr1-179889309-G-A
• rs2245425
• NM_015602.4:c.554-4G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-179889309-G-A
• chr1-179889309-G-C
• chr1-179889309-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PP3_Strong BP6 BA1

The NM_015602.4(TOR1AIP1):​c.554-4G>A variant causes a splice region, 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_015602.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.24
• Publications: 32 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4	c.554-4G>A		splice_region_variant, intron_variant	Intron 2 of 9	ENST00000606911.7	NP_056417.2
TOR1AIP1	NM_001267578.2	c.554-1G>A		splice_acceptor_variant, intron_variant	Intron 2 of 9		NP_001254507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.554-4G>A		splice_region_variant, intron_variant	Intron 2 of 9	1	NM_015602.4	ENSP00000476687.1

Frequencies

GnomAD3 genomes AF: 0.597 AC: 90703 AN: 151850 Hom.: 27499 Cov.: 32

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

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.: 28 AF XY: 0.629 AC XY: 448446 AN XY: 712786

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

GnomAD4 genome AF: 0.597 AC: 90767 AN: 151968 Hom.: 27524 Cov.: 32 AF XY: 0.597 AC XY: 44339 AN XY: 74282

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

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2Y Uncertain:1 Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2017

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2019

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.96
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		4.2
GERP RS		5.3
Mutation Taster		=37/63	disease causing

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

Other links and lift over

dbSNP: rs2245425; hg19: chr1-179858444; COSMIC: COSV108083002;