rs1281378

Variant names:

• chr1-179882939-T-C
• rs1281378
• NM_015602.4:c.437T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-179882939-T-C
• chr1-179882939-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015602.4(TOR1AIP1):​c.437T>C​(p.Met146Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.63 in 1,613,344 control chromosomes in the GnomAD database, including 323,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26558 hom., cov: 32)
  • Exomes 𝑓: 0.63 (296470 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.476
• Publications: 40 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4708805E-6).
• BP6: Variant 1-179882939-T-C is Benign according to our data. Variant chr1-179882939-T-C is described in ClinVar as Benign. ClinVar VariationId is 257699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

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.437T>C	p.Met146Thr	missense	Exon 1 of 10	NP_056417.2
	TOR1AIP1	NM_001267578.2		c.437T>C	p.Met146Thr	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.437T>C	p.Met146Thr	missense	Exon 1 of 10	ENSP00000476687.1	Q5JTV8-1
	TOR1AIP1	ENST00000435319.8	TSL:1	c.74T>C	p.Met25Thr	missense	Exon 1 of 10	ENSP00000393292.3	Q5JTV8-4
	TOR1AIP1	ENST00000271583.7	TSL:5	c.437T>C	p.Met146Thr	missense	Exon 1 of 11	ENSP00000271583.3	J3KN66

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88369 AN: 152014 Hom.: 26537 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.609

GnomAD2 exomes AF: 0.650 AC: 160644 AN: 247320 AF XY: 0.649

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.765

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.760

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.645

GnomAD4 exome AF: 0.635 AC: 927200 AN: 1461212 Hom.: 296470 Cov.: 59 AF XY: 0.636 AC XY: 462164 AN XY: 726872

African (AFR) AF: 0.424 AC: 14185 AN: 33476

American (AMR) AF: 0.759 AC: 33925 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 17091 AN: 26130

East Asian (EAS) AF: 0.753 AC: 29889 AN: 39686

South Asian (SAS) AF: 0.671 AC: 57879 AN: 86240

European-Finnish (FIN) AF: 0.568 AC: 30183 AN: 53134

Middle Eastern (MID) AF: 0.654 AC: 3773 AN: 5766

European-Non Finnish (NFE) AF: 0.631 AC: 702041 AN: 1111740

Other (OTH) AF: 0.633 AC: 38234 AN: 60370

GnomAD4 genome AF: 0.581 AC: 88423 AN: 152132 Hom.: 26558 Cov.: 32 AF XY: 0.581 AC XY: 43214 AN XY: 74366

African (AFR) AF: 0.424 AC: 17598 AN: 41506

American (AMR) AF: 0.677 AC: 10358 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2280 AN: 3470

East Asian (EAS) AF: 0.757 AC: 3899 AN: 5148

South Asian (SAS) AF: 0.673 AC: 3241 AN: 4814

European-Finnish (FIN) AF: 0.567 AC: 6002 AN: 10586

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42982 AN: 67990

Other (OTH) AF: 0.613 AC: 1294 AN: 2112

Alfa AF: 0.622 Hom.: 93923

Bravo AF: 0.584

TwinsUK AF: 0.629 AC: 2333

ALSPAC AF: 0.620 AC: 2389

ESP6500AA AF: 0.444 AC: 1953

ESP6500EA AF: 0.633 AC: 5433

ExAC AF: 0.640 AC: 77614

Asia WGS AF: 0.697 AC: 2422 AN: 3478

EpiCase AF: 0.641

EpiControl AF: 0.640

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2Y (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.94
DANN	Benign	0.66
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N
PhyloP100		0.48
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.033
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.12
ClinPred		0.0043	T
GERP RS		-1.5
PromoterAI		0.070	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.12
gMVP		0.030
Mutation Taster		=99/1	polymorphism (auto)

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: rs1281378; hg19: chr1-179852074; COSMIC: COSV54871057; COSMIC: COSV54871057;