20-31775970-C-T

Variant names:

• chr20-31775970-C-T
• rs771264707
• NM_012112.5:c.712C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_012112.5(TPX2):​c.712C>T​(p.Leu238Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,493,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L238R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TPX2 NM_012112.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.627
• Publications: 0 publications found

Genes affected

TPX2 (HGNC:1249): (TPX2 microtubule nucleation factor) Enables importin-alpha family protein binding activity and protein kinase binding activity. Involved in activation of protein kinase activity; microtubule cytoskeleton organization; and negative regulation of microtubule depolymerization. Located in intercellular bridge; mitotic spindle; and nucleoplasm. Colocalizes with spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

TPX2 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019860566).
• BP6: Variant 20-31775970-C-T is Benign according to our data. Variant chr20-31775970-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3460632.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012112.5. 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
	TPX2	NM_012112.5	MANE Select	c.712C>T	p.Leu238Phe	missense	Exon 8 of 18	NP_036244.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPX2	ENST00000300403.11	TSL:1 MANE Select	c.712C>T	p.Leu238Phe	missense	Exon 8 of 18	ENSP00000300403.6	Q9ULW0-1
	TPX2	ENST00000340513.4	TSL:1	c.712C>T	p.Leu238Phe	missense	Exon 8 of 19	ENSP00000341145.4	Q9ULW0-2
	TPX2	ENST00000934062.1		c.712C>T	p.Leu238Phe	missense	Exon 8 of 19	ENSP00000604121.1

Frequencies

GnomAD3 genomes AF: 0.00000692 AC: 1 AN: 144492 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000731

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: 0.0000704 AC: 17 AN: 241640 AF XY: 0.0000458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000133 AC: 18 AN: 1348622 Hom.: 0 Cov.: 33 AF XY: 0.0000105 AC XY: 7 AN XY: 669476

African (AFR) AF: 0.00 AC: 0 AN: 31716

American (AMR) AF: 0.000426 AC: 17 AN: 39904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22376

East Asian (EAS) AF: 0.00 AC: 0 AN: 26756

South Asian (SAS) AF: 0.00 AC: 0 AN: 82598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5188

European-Non Finnish (NFE) AF: 9.61e-7 AC: 1 AN: 1040942

Other (OTH) AF: 0.00 AC: 0 AN: 53292

GnomAD4 genome AF: 0.00000692 AC: 1 AN: 144492 Hom.: 0 Cov.: 30 AF XY: 0.0000144 AC XY: 1 AN XY: 69670

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40066

American (AMR) AF: 0.0000731 AC: 1 AN: 13678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 4278

South Asian (SAS) AF: 0.00 AC: 0 AN: 4174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66892

Other (OTH) AF: 0.00 AC: 0 AN: 1992

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000906 AC: 11

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.39	N
PhyloP100		0.63
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.080
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.057
MutPred		0.25		Loss of ubiquitination at K236 (P = 0.0896)
MVP		0.068
MPC		0.12
ClinPred		0.38	T
GERP RS		-3.4
Varity_R		0.035
gMVP		0.12
Mutation Taster		=98/2	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: rs771264707; hg19: chr20-30363773;