rs1281378

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 257699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179882939-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4	c.437T>C	p.Met146Thr	missense_variant	1/10	ENST00000606911.7	NP_056417.2
TOR1AIP1	NM_001267578.2	c.437T>C	p.Met146Thr	missense_variant	1/10		NP_001254507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.437T>C	p.Met146Thr	missense_variant	1/10	1	NM_015602.4	ENSP00000476687	P4

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

GnomAD3 exomes AF: 0.650 AC: 160644 AN: 247320 Hom.: 53090 AF XY: 0.649 AC XY: 87457 AN XY: 134744

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 SAS exome AF: 0.669

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

Gnomad4 AFR exome AF: 0.424

Gnomad4 AMR exome AF: 0.759

Gnomad4 ASJ exome AF: 0.654

Gnomad4 EAS exome AF: 0.753

Gnomad4 SAS exome AF: 0.671

Gnomad4 FIN exome AF: 0.568

Gnomad4 NFE exome AF: 0.631

Gnomad4 OTH exome AF: 0.633

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

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.677

Gnomad4 ASJ AF: 0.657

Gnomad4 EAS AF: 0.757

Gnomad4 SAS AF: 0.673

Gnomad4 FIN AF: 0.567

Gnomad4 NFE AF: 0.632

Gnomad4 OTH AF: 0.613

Alfa AF: 0.633 Hom.: 66489

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2Y Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

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;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.52	T;T;T;T;T
MetaRNN	Benign	0.0000015	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;.;N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.4	N;N;.;.;N
REVEL	Benign	0.033
Sift	Benign	1.0	T;T;.;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	.;.;B;.;.
Vest4		0.037
MPC		0.12
ClinPred		0.0043	T
GERP RS		-1.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.12
gMVP		0.030

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