1-179882522-G-A

Position:

• chr1-179882522-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015602.4(TOR1AIP1):​c.20G>A​(p.Arg7Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000383 in 1,306,498 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13713291).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOR1AIP1	NM_015602.4	c.20G>A	p.Arg7Gln	missense_variant	1/10	ENST00000606911.7
TOR1AIP1	NM_001267578.2	c.20G>A	p.Arg7Gln	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.20G>A	p.Arg7Gln	missense_variant	1/10	1	NM_015602.4	P4
	ENST00000610272.1	n.74C>T		non_coding_transcript_exon_variant	1/1
TOR1AIP1	ENST00000271583.7	c.20G>A	p.Arg7Gln	missense_variant	1/11	5		A2
TOR1AIP1	ENST00000528443.6	c.20G>A	p.Arg7Gln	missense_variant	1/10	2		A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000383 AC: 5 AN: 1306498 Hom.: 0 Cov.: 29 AF XY: 0.00000787 AC XY: 5 AN XY: 634944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000632

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.64e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2Y Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 25, 2019

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TOR1AIP1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces arginine with glutamine at codon 7 of the TOR1AIP1 protein (p.Arg7Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.96	N;N;.
REVEL	Benign	0.024
Sift	Benign	0.27	T;T;.
Sift4G	Benign	0.20	T;T;T
Polyphen		0.25	.;.;B
Vest4		0.12
MutPred		0.31		Loss of MoRF binding (P = 0.0122);Loss of MoRF binding (P = 0.0122);Loss of MoRF binding (P = 0.0122);
MVP		0.41
MPC		0.55
ClinPred		0.58	D
GERP RS		2.4
Varity_R		0.044
gMVP		0.19

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

Other links and lift over

dbSNP: rs1647735292; hg19: chr1-179851657;