3-47411889-G-T

Variant names:

• chr3-47411889-G-T
• rs730882229
• NM_015466.4:c.3995G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_015466.4(PTPN23):​c.3995G>T​(p.Arg1332Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1332H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTPN23 NM_015466.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.18
• Publications: 2 publications found

Genes affected

PTPN23 (HGNC:14406): (protein tyrosine phosphatase non-receptor type 23) This gene encodes a member of the non-receptor type protein-tyrosine phosphatase family. The encoded protein may be involved in the regulation of small nuclear ribonucleo protein assembly and pre-mRNA splicing by modifying the survival motor neuron (SMN) complex. The encoded protein additionally plays a role in ciliogenesis and is part of endosomal sorting complex required for transport (ESCRT) pathways. This gene may serve a tumor suppressor function. [provided by RefSeq, Jul 2016]

PTPN23 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 3-47411889-G-T is Pathogenic according to our data. Variant chr3-47411889-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183326.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015466.4. 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
	PTPN23	NM_015466.4	MANE Select	c.3995G>T	p.Arg1332Leu	missense	Exon 21 of 25	NP_056281.1	Q9H3S7
	PTPN23	NM_001304482.2		c.3617G>T	p.Arg1206Leu	missense	Exon 20 of 24	NP_001291411.1	B4DST5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTPN23	ENST00000265562.5	TSL:1 MANE Select	c.3995G>T	p.Arg1332Leu	missense	Exon 21 of 25	ENSP00000265562.4	Q9H3S7
	PTPN23	ENST00000889694.1		c.4022G>T	p.Arg1341Leu	missense	Exon 21 of 25	ENSP00000559753.1
	PTPN23	ENST00000918778.1		c.4004G>T	p.Arg1335Leu	missense	Exon 21 of 25	ENSP00000588837.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity (1)
1	-	-	Seizure;C0557874:Global developmental delay;C4551584:Brain atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.2
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.82
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.89		Loss of MoRF binding (P = 0.0315)
MVP		0.67
MPC		0.42
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.35
gMVP		0.88
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs730882229; hg19: chr3-47453379;