rs2245425

Positions:

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

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PP3_Strong BP6 BA1

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

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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 id is 257701.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr1-179889309-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4	c.554-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000606911.7	NP_056417.2
TOR1AIP1	NM_001267578.2	c.554-1G>A		splice_acceptor_variant			NP_001254507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.554-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015602.4	ENSP00000476687	P4

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

GnomAD3 exomes AF: 0.651 AC: 163002 AN: 250292 Hom.: 54000 AF XY: 0.651 AC XY: 88153 AN XY: 135324

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 SAS exome AF: 0.685

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

Gnomad4 AFR exome AF: 0.492

Gnomad4 AMR exome AF: 0.762

Gnomad4 ASJ exome AF: 0.658

Gnomad4 EAS exome AF: 0.753

Gnomad4 SAS exome AF: 0.686

Gnomad4 FIN exome AF: 0.560

Gnomad4 NFE exome AF: 0.618

Gnomad4 OTH exome AF: 0.633

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

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.682

Gnomad4 ASJ AF: 0.663

Gnomad4 EAS AF: 0.757

Gnomad4 SAS AF: 0.688

Gnomad4 FIN AF: 0.558

Gnomad4 NFE AF: 0.623

Gnomad4 OTH AF: 0.628

Alfa AF: 0.623 Hom.: 42192

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

Uncertain significance, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Jul 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 29, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

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
MutationTaster	Benign	1.0e-16	P;P
GERP RS		5.3

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

LitVar

Other links and lift over

dbSNP: rs2245425; hg19: chr1-179858444;