rs2274955

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-179914055-G-A
• chr1-179914055-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_001267578.2(TOR1AIP1):​c.967+1G>A variant causes a splice donor, intron 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_001267578.2 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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):

• 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: Benign. The variant received -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.032478634 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 1-179914055-G-A is Benign according to our data. Variant chr1-179914055-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0581 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.964+1G>A		splice_donor intron	N/A	NP_056417.2
	TOR1AIP1	NM_001267578.2		c.967+1G>A		splice_donor intron	N/A	NP_001254507.1

Ensembl Transcripts

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

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

GnomAD2 exomes AF: 0.00560 AC: 1400 AN: 250088 AF XY: 0.00502

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33412

American (AMR) AF: 0.00310 AC: 138 AN: 44500

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

East Asian (EAS) AF: 0.0709 AC: 2809 AN: 39630

South Asian (SAS) AF: 0.00178 AC: 153 AN: 85888

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: 0.0000666 AC: 74 AN: 1110870

Other (OTH) AF: 0.00343 AC: 207 AN: 60308

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

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.00124 AC: 19 AN: 15304

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

East Asian (EAS) AF: 0.0638 AC: 331 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4824

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00262 Hom.: 45

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive limb-girdle muscular dystrophy type 2Y (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.4
GERP RS		5.4
Mutation Taster		=86/14	polymorphism (auto)

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; COSMIC: COSV54871203; COSMIC: COSV54871203;