rs2274955

chr1-179914055-G-Achr1-179914055-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 6P and 16B. PVS1_Moderate PP3_Strong BP6_Very_Strong BA1

The NM_015602.4(TOR1AIP1):c.964+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00233 in 1,612,154 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (118 hom.)
• Consequence: TOR1AIP1 NM_015602.4 splice_donor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.35

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 Benign. Variant got -10 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.03196347 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 1-179914055-G-A is Benign according to our data. Variant chr1-179914055-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179914055-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOR1AIP1	NM_015602.4	c.964+1G>A		splice_donor_variant		ENST00000606911.7
TOR1AIP1	NM_001267578.2	c.967+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.964+1G>A		splice_donor_variant		1	NM_015602.4	P4

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 381 AN: 152168 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00560 AC: 1400 AN: 250088 Hom.: 39 AF XY: 0.00502 AC XY: 678 AN XY: 135174

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0674

Gnomad SAS exome AF: 0.00116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00232 AC: 3382 AN: 1459868 Hom.: 118 Cov.: 30 AF XY: 0.00231 AC XY: 1680 AN XY: 726278

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00310

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0709

Gnomad4 SAS exome AF: 0.00178

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152286 Hom.: 9 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74464

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0638

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00279 Hom.: 22

Bravo AF: 0.00323

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00529 AC: 642

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2Y Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 20, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2274955; hg19: chr1-179883190; COSMIC: COSV54871203; COSMIC: COSV54871203;