rs17279712

Positions:

• chr1-179908645-A-C

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.879A>C​(p.Gln293His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 1,612,082 control chromosomes in the GnomAD database, including 3,475 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 0.053 (320 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3155 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0120

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=0.002154529).
• BP6: Variant 1-179908645-A-C is Benign according to our data. Variant chr1-179908645-A-C is described in ClinVar as [Benign]. Clinvar id is 257704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179908645-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.066 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOR1AIP1	NM_015602.4	c.879A>C	p.Gln293His	missense_variant	8/10	ENST00000606911.7
TOR1AIP1	NM_001267578.2	c.882A>C	p.Gln294His	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.879A>C	p.Gln293His	missense_variant	8/10	1	NM_015602.4	P4

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8143 AN: 152174 Hom.: 319 Cov.: 32

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0566

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0676

Gnomad OTH AF: 0.0530

GnomAD3 exomes AF: 0.0555 AC: 13934 AN: 251038 Hom.: 534 AF XY: 0.0567 AC XY: 7701 AN XY: 135722

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.0439

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00294

Gnomad SAS exome AF: 0.0461

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.0647

Gnomad OTH exome AF: 0.0560

GnomAD4 exome AF: 0.0608 AC: 88741 AN: 1459790 Hom.: 3155 Cov.: 30 AF XY: 0.0607 AC XY: 44052 AN XY: 726314

Gnomad4 AFR exome AF: 0.0195

Gnomad4 AMR exome AF: 0.0428

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.00197

Gnomad4 SAS exome AF: 0.0460

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.0642

Gnomad4 OTH exome AF: 0.0546

GnomAD4 genome AF: 0.0535 AC: 8142 AN: 152292 Hom.: 320 Cov.: 32 AF XY: 0.0555 AC XY: 4134 AN XY: 74472

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.0565

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00327

Gnomad4 SAS AF: 0.0398

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.0676

Gnomad4 OTH AF: 0.0520

Alfa AF: 0.0567 Hom.: 601

Bravo AF: 0.0446

TwinsUK AF: 0.0650 AC: 241

ALSPAC AF: 0.0638 AC: 246

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.0623 AC: 536

ExAC AF: 0.0560 AC: 6796

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.0575

EpiControl AF: 0.0549

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	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

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	0.13
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.6
DANN	Benign	0.51
DEOGEN2	Benign	0.065	.;.;T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.63	T;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;.;L;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N;N;.;.;.
REVEL	Benign	0.010
Sift	Benign	0.14	T;T;.;.;.
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.0020	.;.;B;.;.
Vest4		0.11
MutPred		0.23		.;.;Loss of MoRF binding (P = 0.0954);.;.;
MPC		0.097
ClinPred		0.0056	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.39

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: rs17279712; hg19: chr1-179877780; COSMIC: COSV54869246; COSMIC: COSV54869246;