dbSNP rs609521: TOR1AIP1:p.Pro276His (chr1-179907853-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015602.4(TOR1AIP1):c.827C>A(p.Pro276His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P276R) has been classified as Benign.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TOR1AIP1
NM_015602.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.73

Publications

42 publications found

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 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)

TOR1AIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12680963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4 link	c.827C>A	p.Pro276His	missense_variant	Exon 7 of 10	ENST00000606911.7	NP_056417.2	Q5JTV8-1
TOR1AIP1	NM_001267578.2 link	c.830C>A	p.Pro277His	missense_variant	Exon 7 of 10		NP_001254507.1	Q5JTV8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7 link	c.827C>A	p.Pro276His	missense_variant	Exon 7 of 10	1	NM_015602.4	ENSP00000476687.1		Q5JTV8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000429

AC:

AN:

233070

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000940

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1432502

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712472

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32428

American (AMR)

AF:

0.00

AC:

AN:

42148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25348

East Asian (EAS)

AF:

0.00

AC:

AN:

37980

South Asian (SAS)

AF:

0.00

AC:

AN:

81904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1095692

Other (OTH)

AF:

0.00

AC:

AN:

58932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

20398

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.12

.;.;T;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.59

T;T;T;T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.5

.;.;L;.;.

PhyloP100

1.7

PrimateAI

Benign

0.26

PROVEAN

Benign

-2.3

N;N;.;.;.

REVEL

Benign

0.066

Sift

Uncertain

0.0050

D;D;.;.;.

Sift4G

Uncertain

0.030

D;T;D;T;T

Polyphen

0.0020

.;.;B;.;.

Vest4

0.14

MutPred

0.61

.;.;Gain of catalytic residue at P276 (P = 0.0679);.;.;

MVP

0.48

MPC

0.12

ClinPred

0.17

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

gMVP

0.22

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over