rs609521

Variant names:

• chr1-179907853-C-G
• rs609521
• NM_015602.4:c.827C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-179907853-C-G
• chr1-179907853-C-A
• chr1-179907853-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015602.4(TOR1AIP1):​c.827C>G​(p.Pro276Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,574,268 control chromosomes in the GnomAD database, including 309,637 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P276S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.56 (24612 hom., cov: 25)
  • Exomes 𝑓: 0.63 (285025 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.73
• Publications: 42 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.02066E-6).
• BP6: Variant 1-179907853-C-G is Benign according to our data. Variant chr1-179907853-C-G is described in ClinVar as Benign. ClinVar VariationId is 257703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

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.827C>G	p.Pro276Arg	missense	Exon 7 of 10	NP_056417.2
	TOR1AIP1	NM_001267578.2		c.830C>G	p.Pro277Arg	missense	Exon 7 of 10	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.827C>G	p.Pro276Arg	missense	Exon 7 of 10	ENSP00000476687.1	Q5JTV8-1
	TOR1AIP1	ENST00000435319.8	TSL:1	c.464C>G	p.Pro155Arg	missense	Exon 7 of 10	ENSP00000393292.3	Q5JTV8-4
	TOR1AIP1	ENST00000271583.7	TSL:5	c.830C>G	p.Pro277Arg	missense	Exon 7 of 11	ENSP00000271583.3	J3KN66

Frequencies

GnomAD3 genomes AF: 0.559 AC: 82918 AN: 148400 Hom.: 24597 Cov.: 25

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.670

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.660

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.599

GnomAD2 exomes AF: 0.631 AC: 147035 AN: 233070 AF XY: 0.633

Gnomad AFR exome AF: 0.336

Gnomad AMR exome AF: 0.756

Gnomad ASJ exome AF: 0.653

Gnomad EAS exome AF: 0.746

Gnomad FIN exome AF: 0.563

Gnomad NFE exome AF: 0.626

Gnomad OTH exome AF: 0.629

GnomAD4 exome AF: 0.628 AC: 895629 AN: 1425810 Hom.: 285025 Cov.: 28 AF XY: 0.630 AC XY: 446491 AN XY: 709270

African (AFR) AF: 0.338 AC: 10890 AN: 32230

American (AMR) AF: 0.751 AC: 31398 AN: 41808

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 16369 AN: 25228

East Asian (EAS) AF: 0.749 AC: 28357 AN: 37878

South Asian (SAS) AF: 0.659 AC: 53563 AN: 81308

European-Finnish (FIN) AF: 0.560 AC: 29212 AN: 52172

Middle Eastern (MID) AF: 0.652 AC: 3670 AN: 5628

European-Non Finnish (NFE) AF: 0.628 AC: 685529 AN: 1090874

Other (OTH) AF: 0.624 AC: 36641 AN: 58684

GnomAD4 genome AF: 0.559 AC: 82942 AN: 148458 Hom.: 24612 Cov.: 25 AF XY: 0.559 AC XY: 40226 AN XY: 72020

African (AFR) AF: 0.347 AC: 14067 AN: 40500

American (AMR) AF: 0.667 AC: 9835 AN: 14756

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2268 AN: 3454

East Asian (EAS) AF: 0.758 AC: 3850 AN: 5082

South Asian (SAS) AF: 0.669 AC: 3184 AN: 4758

European-Finnish (FIN) AF: 0.565 AC: 5164 AN: 9136

Middle Eastern (MID) AF: 0.680 AC: 193 AN: 284

European-Non Finnish (NFE) AF: 0.630 AC: 42575 AN: 67532

Other (OTH) AF: 0.603 AC: 1238 AN: 2052

Alfa AF: 0.612 Hom.: 20398

Bravo AF: 0.559

ESP6500AA AF: 0.366 AC: 1613

ESP6500EA AF: 0.629 AC: 5413

ExAC AF: 0.632 AC: 76750

Asia WGS AF: 0.685 AC: 2380 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.066
Sift	Benign	0.13	T
Sift4G	Uncertain	0.050	T
Polyphen		0.17	B
Vest4		0.13
MPC		0.15
ClinPred		0.028	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.26
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs609521; hg19: chr1-179876988; COSMIC: COSV54872578; COSMIC: COSV54872578;