chr1-179882527-G-A

Position:

• chr1-179882527-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015602.4(TOR1AIP1):​c.25G>A​(p.Glu9Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000762 in 1,312,182 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 (★). Synonymous variant affecting the same amino acid position (i.e. E9E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.65

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3121608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4	c.25G>A	p.Glu9Lys	missense_variant	1/10	ENST00000606911.7	NP_056417.2
TOR1AIP1	NM_001267578.2	c.25G>A	p.Glu9Lys	missense_variant	1/10		NP_001254507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.25G>A	p.Glu9Lys	missense_variant	1/10	1	NM_015602.4	ENSP00000476687.1
TOR1AIP1	ENST00000271583.7	c.25G>A	p.Glu9Lys	missense_variant	1/11	5		ENSP00000271583.3
TOR1AIP1	ENST00000528443.6	c.25G>A	p.Glu9Lys	missense_variant	1/10	2		ENSP00000435365.2
ENSG00000272906	ENST00000610272.1	n.69C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.62e-7 AC: 1 AN: 1312182 Hom.: 0 Cov.: 29 AF XY: 0.00000157 AC XY: 1 AN XY: 638406

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.61e-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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2022

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: "Tolerated"; 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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 9 of the TOR1AIP1 protein (p.Glu9Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;.;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Benign	0.049
Sift	Uncertain	0.018	D;D;.
Sift4G	Benign	0.11	T;T;T
Polyphen		0.78	.;.;P
Vest4		0.33
MutPred		0.34		Gain of glycosylation at E9 (P = 0.0201);Gain of glycosylation at E9 (P = 0.0201);Gain of glycosylation at E9 (P = 0.0201);
MVP		0.62
MPC		0.54
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.27
gMVP		0.25

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: rs1647735595; hg19: chr1-179851662;