rs146976883

Variant names:

• chr1-179882572-C-G
• rs146976883
• NM_015602.4:c.70C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015602.4(TOR1AIP1):​c.70C>G​(p.Pro24Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,517,228 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (11 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.27
• Publications: 3 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]

TOR1AIP2 (HGNC:24055): (torsin 1A interacting protein 2) One of the two protein isoforms encoded by this gene is a type II integral membrane protein found in the endoplasmic reticulum (ER). The encoded protein is a cofactor for the ATPase TorsinA, regulating the amount of TorsinA present in the ER compared to that found in the nuclear envelope. Defects in this protein are a cause of early onset primary dystonia, a neuromuscular disease. The other isoform encoded by this gene is an interferon alpha responsive protein whose cellular role has yet to be determined. [provided by RefSeq, Mar 2017]

ENSG00000272906 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007002741).
• BP6: Variant 1-179882572-C-G is Benign according to our data. Variant chr1-179882572-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476288.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00223 (340/152210) while in subpopulation NFE AF = 0.00348 (237/68006). AF 95% confidence interval is 0.00312. There are 3 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.70C>G	p.Pro24Ala	missense	Exon 1 of 10	NP_056417.2
	TOR1AIP1	NM_001267578.2		c.70C>G	p.Pro24Ala	missense	Exon 1 of 10	NP_001254507.1	Q5JTV8-3
	LOC139427322	NM_001436163.1		c.*179C>G		downstream_gene	N/A	NP_001423092.1	A0AAQ5BH39

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1AIP1	ENST00000606911.7	TSL:1 MANE Select	c.70C>G	p.Pro24Ala	missense	Exon 1 of 10	ENSP00000476687.1	Q5JTV8-1
	TOR1AIP1	ENST00000271583.7	TSL:5	c.70C>G	p.Pro24Ala	missense	Exon 1 of 11	ENSP00000271583.3	J3KN66
	TOR1AIP1	ENST00000528443.6	TSL:2	c.70C>G	p.Pro24Ala	missense	Exon 1 of 10	ENSP00000435365.2	Q5JTV8-3

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 340 AN: 152092 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00509

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00220 AC: 353 AN: 160708 AF XY: 0.00218

Gnomad AFR exome AF: 0.000537

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00362

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.00300 AC: 4089 AN: 1365018 Hom.: 11 Cov.: 29 AF XY: 0.00298 AC XY: 1995 AN XY: 669738

African (AFR) AF: 0.000465 AC: 14 AN: 30126

American (AMR) AF: 0.000779 AC: 22 AN: 28256

Ashkenazi Jewish (ASJ) AF: 0.00324 AC: 64 AN: 19756

East Asian (EAS) AF: 0.00 AC: 0 AN: 38644

South Asian (SAS) AF: 0.000400 AC: 28 AN: 70006

European-Finnish (FIN) AF: 0.00324 AC: 157 AN: 48502

Middle Eastern (MID) AF: 0.000389 AC: 2 AN: 5142

European-Non Finnish (NFE) AF: 0.00342 AC: 3659 AN: 1068470

Other (OTH) AF: 0.00255 AC: 143 AN: 56116

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152210 Hom.: 3 Cov.: 31 AF XY: 0.00226 AC XY: 168 AN XY: 74418

African (AFR) AF: 0.000554 AC: 23 AN: 41540

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00509 AC: 54 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00348 AC: 237 AN: 68006

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00371 Hom.: 0

Bravo AF: 0.00194

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00223 AC: 19

ExAC AF: 0.00211 AC: 249

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Autosomal recessive limb-girdle muscular dystrophy type 2Y (3)
-	1	-	Inborn genetic diseases (1)
-	-	1	TOR1AIP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.72
MPC		0.51
ClinPred		0.034	T
GERP RS		5.3
PromoterAI		0.17	Neutral
Varity_R		0.47
gMVP		0.17
Mutation Taster		=84/16	polymorphism

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: rs146976883; hg19: chr1-179851707; COSMIC: COSV99056338; COSMIC: COSV99056338;