rs146976883

Positions:

chr1-179882572-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000606911.7(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
ENST00000606911.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.27

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 476288.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=4}. Variant chr1-179882572-C-G is described in Lovd as [Likely_benign]. Variant chr1-179882572-C-G is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4 linkuse as main transcript	c.70C>G	p.Pro24Ala	missense_variant	1/10	ENST00000606911.7	NP_056417.2
TOR1AIP1	NM_001267578.2 linkuse as main transcript	c.70C>G	p.Pro24Ala	missense_variant	1/10		NP_001254507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7 linkuse as main transcript	c.70C>G	p.Pro24Ala	missense_variant	1/10	1	NM_015602.4	ENSP00000476687	P4	Q5JTV8-1
	ENST00000610272.1 linkuse as main transcript	n.24G>C		non_coding_transcript_exon_variant	1/1
TOR1AIP1	ENST00000271583.7 linkuse as main transcript	c.70C>G	p.Pro24Ala	missense_variant	1/11	5		ENSP00000271583	A2
TOR1AIP1	ENST00000528443.6 linkuse as main transcript	c.70C>G	p.Pro24Ala	missense_variant	1/10	2		ENSP00000435365	A2	Q5JTV8-3

Frequencies

GnomAD3 genomes

AF:

0.00224

AC:

340

AN:

152092

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00220

AC:

353

AN:

160708

Hom.:

AF XY:

0.00218

AC XY:

187

AN XY:

85886

show subpopulations

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 SAS exome

AF:

0.000428

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.:

Cov.:

AF XY:

0.00298

AC XY:

1995

AN XY:

669738

show subpopulations

Gnomad4 AFR exome

AF:

0.000465

Gnomad4 AMR exome

AF:

0.000779

Gnomad4 ASJ exome

AF:

0.00324

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000400

Gnomad4 FIN exome

AF:

0.00324

Gnomad4 NFE exome

AF:

0.00342

Gnomad4 OTH exome

AF:

0.00255

GnomAD4 genome

AF:

0.00223

AC:

340

AN:

152210

Hom.:

Cov.:

AF XY:

0.00226

AC XY:

168

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00509

Gnomad4 NFE

AF:

0.00348

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00371

Hom.:

Bravo

AF:

0.00194

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00223

AC:

ExAC

AF:

0.00211

AC:

249

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2022	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ENSG00000272906: BS2; TOR1AIP1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2Y

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 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	Jul 23, 2021	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

The c.70C>G (p.P24A) alteration is located in exon 1 (coding exon 1) of the TOR1AIP1 gene. This alteration results from a C to G substitution at nucleotide position 70, causing the proline (P) at amino acid position 24 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

TOR1AIP1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;.;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.0070

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

2.0

M;.;M

MutationTaster

Benign

0.84

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.1

D;D;.

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;.;D

Vest4

0.56

MVP

0.72

MPC

0.51

ClinPred

0.034

GERP RS

5.3

Varity_R

0.47

gMVP

0.17

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over