1-179882549-G-T

Position:

chr1-179882549-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015602.4(TOR1AIP1):c.47G>T(p.Gly16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000133 in 1,499,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

TOR1AIP1
NM_015602.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.883

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:

ENSG00000272906 (HGNC:):

ENSG00000272906 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06487548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4 linkuse as main transcript	c.47G>T	p.Gly16Val	missense_variant	1/10	ENST00000606911.7	NP_056417.2	Q5JTV8-1
TOR1AIP1	NM_001267578.2 linkuse as main transcript	c.47G>T	p.Gly16Val	missense_variant	1/10		NP_001254507.1	Q5JTV8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TOR1AIP1	ENST00000606911.7 linkuse as main transcript	c.47G>T	p.Gly16Val	missense_variant	1/10	1	NM_015602.4	ENSP00000476687.1	Q5JTV8-1
TOR1AIP1	ENST00000271583.7 linkuse as main transcript	c.47G>T	p.Gly16Val	missense_variant	1/11	5		ENSP00000271583.3	J3KN66
TOR1AIP1	ENST00000528443.6 linkuse as main transcript	c.47G>T	p.Gly16Val	missense_variant	1/10	2		ENSP00000435365.2	Q5JTV8-3
ENSG00000272906	ENST00000610272.1 linkuse as main transcript	n.47C>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.42e-7

AC:

AN:

1347438

Hom.:

Cov.:

AF XY:

0.00000152

AC XY:

AN XY:

659790

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000394

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.47G>T (p.G16V) alteration is located in exon 1 (coding exon 1) of the TOR1AIP1 gene. This alteration results from a G to T substitution at nucleotide position 47, causing the glycine (G) at amino acid position 16 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive limb-girdle muscular dystrophy type 2Y

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2022

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1388867). This variant has not been reported in the literature in individuals affected with TOR1AIP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 16 of the TOR1AIP1 protein (p.Gly16Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.077

.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.0061

MetaRNN

Benign

0.065

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.82

N;N;.

REVEL

Benign

0.042

Sift

Benign

0.086

T;T;.

Sift4G

Benign

0.12

T;T;T

Polyphen

0.0070

.;.;B

Vest4

0.16

MutPred

0.29

Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);Loss of disorder (P = 0.0362);

MVP

0.25

MPC

0.13

ClinPred

0.096

GERP RS

-1.3

Varity_R

0.045

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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