1-179882657-A-T

Variant names:

• chr1-179882657-A-T
• rs139690983
• NM_015602.4:c.155A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_015602.4(TOR1AIP1):​c.155A>T​(p.Gln52Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,584,166 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q52Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00066 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0510
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057226717).
• BP6: Variant 1-179882657-A-T is Benign according to our data. Variant chr1-179882657-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542852.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000665 (101/151978) while in subpopulation AFR AF = 0.00241 (100/41454). AF 95% confidence interval is 0.00203. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.155A>T	p.Gln52Leu	missense	Exon 1 of 10	NP_056417.2
	TOR1AIP1	NM_001267578.2		c.155A>T	p.Gln52Leu	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.155A>T	p.Gln52Leu	missense	Exon 1 of 10	ENSP00000476687.1	Q5JTV8-1
	TOR1AIP1	ENST00000271583.7	TSL:5	c.155A>T	p.Gln52Leu	missense	Exon 1 of 11	ENSP00000271583.3	J3KN66
	TOR1AIP1	ENST00000528443.6	TSL:2	c.155A>T	p.Gln52Leu	missense	Exon 1 of 10	ENSP00000435365.2	Q5JTV8-3

Frequencies

GnomAD3 genomes AF: 0.000672 AC: 102 AN: 151860 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000260 AC: 59 AN: 226836 AF XY: 0.000187

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.000130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000969

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000852 AC: 122 AN: 1432188 Hom.: 0 Cov.: 30 AF XY: 0.0000606 AC XY: 43 AN XY: 710056

African (AFR) AF: 0.00305 AC: 99 AN: 32406

American (AMR) AF: 0.000173 AC: 7 AN: 40544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39490

South Asian (SAS) AF: 0.00 AC: 0 AN: 82388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52086

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5558

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1096968

Other (OTH) AF: 0.000204 AC: 12 AN: 58894

GnomAD4 genome AF: 0.000665 AC: 101 AN: 151978 Hom.: 1 Cov.: 31 AF XY: 0.000713 AC XY: 53 AN XY: 74298

African (AFR) AF: 0.00241 AC: 100 AN: 41454

American (AMR) AF: 0.0000656 AC: 1 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000734 Hom.: 0

Bravo AF: 0.000759

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.051
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.041
Sift	Benign	0.035	D
Sift4G	Benign	0.087	T
Polyphen		0.16	B
Vest4		0.11
MVP		0.36
MPC		0.099
ClinPred		0.048	T
GERP RS		-0.83
PromoterAI		-0.062	Neutral
Varity_R		0.13
gMVP		0.057
Mutation Taster		=91/9	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: rs139690983; hg19: chr1-179851792;