1-179882506-G-A

Variant summary

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

The NM_015602.4(TOR1AIP1):c.4G>A(p.Ala2Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000153 in 1,303,700 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.14

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOR1AIP1	NM_015602.4	c.4G>A	p.Ala2Thr	missense_variant	1/10	ENST00000606911.7
TOR1AIP1	NM_001267578.2	c.4G>A	p.Ala2Thr	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.4G>A	p.Ala2Thr	missense_variant	1/10	1	NM_015602.4	P4
	ENST00000610272.1	n.90C>T		non_coding_transcript_exon_variant	1/1
TOR1AIP1	ENST00000271583.7	c.4G>A	p.Ala2Thr	missense_variant	1/11	5		A2
TOR1AIP1	ENST00000528443.6	c.4G>A	p.Ala2Thr	missense_variant	1/10	2		A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1303700 Hom.: 0 Cov.: 29 AF XY: 0.00000158 AC XY: 1 AN XY: 633322

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000510

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000159

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000981 AC: 1

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

Jul 29, 2022

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2 of the TOR1AIP1 protein (p.Ala2Thr). This variant has not been reported in the literature in individuals affected with TOR1AIP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	0.22
BayesDel_addAF	Benign	0.0042	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.43	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	0.89	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	.;.;D
Vest4		0.30
MutPred		0.29		Gain of phosphorylation at A2 (P = 0.0205);Gain of phosphorylation at A2 (P = 0.0205);Gain of phosphorylation at A2 (P = 0.0205);
MVP		0.76
MPC		0.51
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.18
gMVP		0.28

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: rs762432523; hg19: chr1-179851641;