1-179882509-G-A

Position:

• chr1-179882509-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015602.4(TOR1AIP1):​c.7G>A​(p.Gly3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,302,798 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: 0.0000015 (0 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.17

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 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=0.013346314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4	c.7G>A	p.Gly3Ser	missense_variant	1/10	ENST00000606911.7	NP_056417.2
TOR1AIP1	NM_001267578.2	c.7G>A	p.Gly3Ser	missense_variant	1/10		NP_001254507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.7G>A	p.Gly3Ser	missense_variant	1/10	1	NM_015602.4	ENSP00000476687.1
TOR1AIP1	ENST00000271583.7	c.7G>A	p.Gly3Ser	missense_variant	1/11	5		ENSP00000271583.3
TOR1AIP1	ENST00000528443.6	c.7G>A	p.Gly3Ser	missense_variant	1/10	2		ENSP00000435365.2
ENSG00000272906	ENST00000610272.1	n.87C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000248 AC: 2 AN: 80590 Hom.: 0 AF XY: 0.0000492 AC XY: 2 AN XY: 40662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000193

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1302798 Hom.: 0 Cov.: 29 AF XY: 0.00000316 AC XY: 2 AN XY: 632630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000102

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 Cov.: 31

Bravo AF: 0.0000151

ExAC AF: 0.0000681 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2Y Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3 of the TOR1AIP1 protein (p.Gly3Ser). This variant is present in population databases (rs763660412, gnomAD 0.02%). 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: "Possibly 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	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	.;.;T
Eigen	Benign	-0.060
Eigen_PC	Benign	-0.029
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N;N;.
REVEL	Benign	0.062
Sift	Uncertain	0.0060	D;D;.
Sift4G	Uncertain	0.045	D;T;D
Polyphen		0.64	.;.;P
Vest4		0.15
MutPred		0.29		Loss of catalytic residue at G3 (P = 0.0058);Loss of catalytic residue at G3 (P = 0.0058);Loss of catalytic residue at G3 (P = 0.0058);
MVP		0.59
MPC		0.33
ClinPred		0.51	D
GERP RS		3.4
Varity_R		0.11
gMVP		0.14

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: rs763660412; hg19: chr1-179851644;