1-179882930-C-G

Variant names:

• chr1-179882930-C-G
• rs141391430
• NM_015602.4:c.428C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015602.4(TOR1AIP1):​c.428C>G​(p.Ser143Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S143F) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63
• Publications: 0 publications found

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]

TOR1AIP2 (HGNC:24055): (torsin 1A interacting protein 2) One of the two protein isoforms encoded by this gene is a type II integral membrane protein found in the endoplasmic reticulum (ER). The encoded protein is a cofactor for the ATPase TorsinA, regulating the amount of TorsinA present in the ER compared to that found in the nuclear envelope. Defects in this protein are a cause of early onset primary dystonia, a neuromuscular disease. The other isoform encoded by this gene is an interferon alpha responsive protein whose cellular role has yet to be determined. [provided by RefSeq, Mar 2017]

ENSG00000272906 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34131002).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015602.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1AIP1	NM_015602.4	MANE Select	c.428C>G	p.Ser143Cys	missense	Exon 1 of 10	NP_056417.2
	TOR1AIP1	NM_001267578.2		c.428C>G	p.Ser143Cys	missense	Exon 1 of 10	NP_001254507.1	Q5JTV8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOR1AIP1	ENST00000606911.7	TSL:1 MANE Select	c.428C>G	p.Ser143Cys	missense	Exon 1 of 10	ENSP00000476687.1	Q5JTV8-1
	TOR1AIP1	ENST00000435319.8	TSL:1	c.65C>G	p.Ser22Cys	missense	Exon 1 of 10	ENSP00000393292.3	Q5JTV8-4
	TOR1AIP1	ENST00000271583.7	TSL:5	c.428C>G	p.Ser143Cys	missense	Exon 1 of 11	ENSP00000271583.3	J3KN66

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461688 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727146

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.079
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.6
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.075
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.19
MutPred		0.50		Gain of catalytic residue at P142 (P = 0.0123)
MVP		0.56
MPC		0.44
ClinPred		0.94	D
GERP RS		3.3
PromoterAI		-0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.046
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs141391430; hg19: chr1-179852065;