1-179882557-G-A

Position:

• chr1-179882557-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.55G>A​(p.Val19Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000797 in 1,505,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V19D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000037 (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]

ENSG00000272906 (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=0.23154187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4	c.55G>A	p.Val19Ile	missense_variant	1/10	ENST00000606911.7	NP_056417.2
TOR1AIP1	NM_001267578.2	c.55G>A	p.Val19Ile	missense_variant	1/10		NP_001254507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.55G>A	p.Val19Ile	missense_variant	1/10	1	NM_015602.4	ENSP00000476687.1
TOR1AIP1	ENST00000271583.7	c.55G>A	p.Val19Ile	missense_variant	1/11	5		ENSP00000271583.3
TOR1AIP1	ENST00000528443.6	c.55G>A	p.Val19Ile	missense_variant	1/10	2		ENSP00000435365.2
ENSG00000272906	ENST00000610272.1	n.39C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000369 AC: 5 AN: 1353756 Hom.: 0 Cov.: 29 AF XY: 0.00000302 AC XY: 2 AN XY: 663262

Gnomad4 AFR exome AF: 0.000168

Gnomad4 AMR exome AF: 0.00

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: 0.0000460 AC: 7 AN: 152140 Hom.: 0 Cov.: 31 AF XY: 0.0000807 AC XY: 6 AN XY: 74332

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

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: 0.0000529

ExAC AF: 0.00000860 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2022

ClinVar contains an entry for this variant (Variation ID: 1063183). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 19 of the TOR1AIP1 protein (p.Val19Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	2.0	M;.;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.43	N;N;.
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.23
MutPred		0.46		Gain of catalytic residue at P21 (P = 0.0344);Gain of catalytic residue at P21 (P = 0.0344);Gain of catalytic residue at P21 (P = 0.0344);
MVP		0.57
MPC		0.45
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.19
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs760887402; hg19: chr1-179851692;