Genetic Variant PTPN23:p.Met1? (chr3-47381098-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_015466.4(PTPN23):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000704 in 1,421,326 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PTPN23
NM_015466.4 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.58

Publications

0 publications found

Variant links:

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 links:

PTPN23-DT (HGNC:55397): (PTPN23 divergent transcript)

PTPN23-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 7 codons. Genomic position: 47381115. Lost 0.004 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN23	NM_015466.4	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 25	NP_056281.1	Q9H3S7
PTPN23	NM_001304482.2		c.-249T>C		5_prime_UTR	Exon 1 of 24	NP_001291411.1	B4DST5
PTPN23-DT	NR_185912.1		n.395A>G		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PTPN23	ENST00000265562.5	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 25	ENSP00000265562.4	Q9H3S7
PTPN23	ENST00000889694.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 25	ENSP00000559753.1
PTPN23	ENST00000918778.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 25	ENSP00000588837.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1421326

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703710

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32230

American (AMR)

AF:

0.00

AC:

AN:

38620

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25368

East Asian (EAS)

AF:

0.00

AC:

AN:

36810

South Asian (SAS)

AF:

0.00

AC:

AN:

81034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1092866

Other (OTH)

AF:

0.00

AC:

AN:

58840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-1.1

PhyloP100

5.6

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.91

MVP

0.80

ClinPred

1.0

GERP RS

4.5

PromoterAI

-0.39

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.8

Varity_R

0.95

gMVP

0.69

Mutation Taster

=38/162

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over