1-179914055-G-C

Variant names:

• chr1-179914055-G-C
• rs2274955
• NM_015602.4:c.964+1G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_015602.4(TOR1AIP1):​c.964+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000031 in 1,612,054 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TOR1AIP1 NM_015602.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.35
• Publications: 6 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):

• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.032534245 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015602.4. 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.964+1G>C		splice_donor intron	N/A	NP_056417.2
	TOR1AIP1	NM_001267578.2		c.967+1G>C		splice_donor intron	N/A	NP_001254507.1	Q5JTV8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1AIP1	ENST00000606911.7	TSL:1 MANE Select	c.964+1G>C		splice_donor intron	N/A	ENSP00000476687.1	Q5JTV8-1
	TOR1AIP1	ENST00000435319.8	TSL:1	c.601+1G>C		splice_donor intron	N/A	ENSP00000393292.3	Q5JTV8-4
	TOR1AIP1	ENST00000271583.7	TSL:5	c.1012+1G>C		splice_donor intron	N/A	ENSP00000271583.3	J3KN66

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000800 AC: 2 AN: 250088 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459886 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726286

African (AFR) AF: 0.0000599 AC: 2 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110870

Other (OTH) AF: 0.0000166 AC: 1 AN: 60314

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 45

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2Y (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		4.4
GERP RS		5.4
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs2274955; hg19: chr1-179883190;