rs141391430

Positions:

• chr1-179882930-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015602.4(TOR1AIP1):​c.428C>T​(p.Ser143Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,614,032 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00058 (3 hom.)
• Consequence: TOR1AIP1 NM_015602.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.63

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 -18 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity TOIP1_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.0076898634).
• BP6: Variant 1-179882930-C-T is Benign according to our data. Variant chr1-179882930-C-T is described in ClinVar as [Benign]. Clinvar id is 476285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000656 (100/152344) while in subpopulation NFE AF= 0.000691 (47/68030). AF 95% confidence interval is 0.000534. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TOR1AIP1	NM_015602.4	c.428C>T	p.Ser143Phe	missense_variant	1/10	ENST00000606911.7	NP_056417.2
TOR1AIP1	NM_001267578.2	c.428C>T	p.Ser143Phe	missense_variant	1/10		NP_001254507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TOR1AIP1	ENST00000606911.7	c.428C>T	p.Ser143Phe	missense_variant	1/10	1	NM_015602.4	ENSP00000476687	P4

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152226 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000857 AC: 213 AN: 248556 Hom.: 2 AF XY: 0.000821 AC XY: 111 AN XY: 135264

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.000659

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000585 AC: 855 AN: 1461688 Hom.: 3 Cov.: 30 AF XY: 0.000587 AC XY: 427 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00987

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000442

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.000656 AC: 100 AN: 152344 Hom.: 0 Cov.: 31 AF XY: 0.000537 AC XY: 40 AN XY: 74502

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.000638

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000791 AC: 96

EpiCase AF: 0.000927

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Oct 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.40	.;.;T;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0077	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.5	M;.;M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.4	N;N;.;.;D
REVEL	Benign	0.078
Sift	Benign	0.079	T;T;.;.;T
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.059	.;.;B;.;.
Vest4		0.20
MVP		0.49
MPC		0.12
ClinPred		0.022	T
GERP RS		3.3
Varity_R		0.10
gMVP		0.049

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: rs141391430; hg19: chr1-179852065; COSMIC: COSV54869632; COSMIC: COSV54869632;