rs149690630

chr1-179917634-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_015602.4(TOR1AIP1):c.1147G>A(p.Asp383Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00248 in 1,614,166 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (10 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.79

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011664093).
• BP6: Variant 1-179917634-G-A is Benign according to our data. Variant chr1-179917634-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-179917634-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00206 (314/152282) while in subpopulation NFE AF= 0.00378 (257/68024). AF 95% confidence interval is 0.0034. There are 1 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOR1AIP1	NM_015602.4	c.1147G>A	p.Asp383Asn	missense_variant	10/10	ENST00000606911.7
TOR1AIP1	NM_001267578.2	c.1150G>A	p.Asp384Asn	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.1147G>A	p.Asp383Asn	missense_variant	10/10	1	NM_015602.4	P4

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00163 AC: 409 AN: 251350 Hom.: 0 AF XY: 0.00183 AC XY: 249 AN XY: 135836

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00290

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00252 AC: 3688 AN: 1461884 Hom.: 10 Cov.: 29 AF XY: 0.00255 AC XY: 1858 AN XY: 727248

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00298

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00206 AC: 314 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74462

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00296 Hom.: 3

Bravo AF: 0.00155

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00168 AC: 204

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00225

ClinVar

Significance: Likely 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

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TOR1AIP1: BP4, BS2 -

TOR1AIP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	-0.090
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N;N;.;.
REVEL	Benign	0.035
Sift	Benign	0.20	T;T;.;.
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.23	.;.;B;.
Vest4		0.20
MVP		0.48
MPC		0.51
ClinPred		0.020	T
GERP RS		4.0
Varity_R		0.063
gMVP		0.52

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: rs149690630; hg19: chr1-179886769;