Genetic Variant PUM3:p.Leu629Met (chr9-2804393-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014878.5(PUM3):c.1885T>A(p.Leu629Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PUM3
NM_014878.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.183

Publications

0 publications found

Variant links:

Genes affected

PUM3 (HGNC:29676): (pumilio RNA binding family member 3) Enables RNA binding activity. Involved in regulation of protein ADP-ribosylation. Located in chromosome; endoplasmic reticulum; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

PUM3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18151617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PUM3	NM_014878.5 link	c.1885T>A	p.Leu629Met	missense_variant	Exon 18 of 18	ENST00000397885.3	NP_055693.4	Q15397

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PUM3	ENST00000397885.3 link	c.1885T>A	p.Leu629Met	missense_variant	Exon 18 of 18	1	NM_014878.5	ENSP00000380982.2	Q15397
PUM3	ENST00000382032.3 link	n.232T>A		non_coding_transcript_exon_variant	Exon 2 of 2	2
PUM3	ENST00000490444.2 link	n.88T>A		non_coding_transcript_exon_variant	Exon 2 of 4	5		ENSP00000474467.1	S4R3K8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727104

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111914

Other (OTH)

AF:

0.00

AC:

AN:

60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.69

M_CAP

Benign

0.021

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.77

PhyloP100

0.18

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.88

REVEL

Benign

0.20

Sift

Benign

0.036

Sift4G

Benign

0.076

Polyphen

0.90

Vest4

0.40

MutPred

0.38

Gain of methylation at K633 (P = 0.0543);

MVP

0.030

MPC

0.013

ClinPred

0.88

GERP RS

-3.4

Varity_R

0.19

gMVP

0.32

Mutation Taster

=78/22

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over