Genetic Variant POU3F3:p.Pro102Leu (chr2-104855815-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_006236.3(POU3F3):c.305C>T(p.Pro102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POU3F3
NM_006236.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.18

Publications

0 publications found

Variant links:

Genes affected

POU3F3 (HGNC:9216): (POU class 3 homeobox 3) This gene encodes a POU-domain containing protein that functions as a transcription factor. The encoded protein recognizes an octamer sequence in the DNA of target genes. This protein may play a role in development of the nervous system. [provided by RefSeq, Apr 2015]

POU3F3 links:

ENSG00000269707 (HGNC:):

ENSG00000269707 links:

PANTR1 (HGNC:49513): (POU3F3 adjacent non-coding transcript 1) Predicted to act upstream of or within regulation of gene expression. [provided by Alliance of Genome Resources, Apr 2022]

PANTR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.0416 (below the threshold of 3.09). Trascript score misZ: -0.11043 (below the threshold of 3.09). GenCC associations: The gene is linked to snijders blok-fisher syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.37211442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F3	NM_006236.3 link	c.305C>T	p.Pro102Leu	missense_variant	Exon 1 of 1	ENST00000361360.4	NP_006227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU3F3	ENST00000361360.4 link	c.305C>T	p.Pro102Leu	missense_variant	Exon 1 of 1	6	NM_006236.3	ENSP00000355001.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1041100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

509578

African (AFR)

AF:

0.00

AC:

AN:

19668

American (AMR)

AF:

0.00

AC:

AN:

11012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11886

East Asian (EAS)

AF:

0.00

AC:

AN:

14510

South Asian (SAS)

AF:

0.00

AC:

AN:

42186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2954

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

886734

Other (OTH)

AF:

0.00

AC:

AN:

36752

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 30, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The alteration results in an amino acid change:_x000D_ _x000D_ The c.305C>T (p.P102L) alteration is located in coding exon 1 of the POU3F3 gene. This alteration results from a C to T substitution at nucleotide position 305, causing the proline (P) at amino acid position 102 to be replaced by a leucine (L). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the POU3F3 c.305C>T alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.P102 amino acid is somewhat conserved in available vertebrate species on limited sequence alignment. The alteration is predicted tolerated by in silico modeling:_x000D_ _x000D_ The p.P102L alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.0091

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.37

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.1

PhyloP100

3.2

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.24

MutPred

0.38

Loss of glycosylation at P102 (P = 0.0214);

MVP

0.75

ClinPred

0.79

GERP RS

0.57

Varity_R

0.16

gMVP

0.31

Mutation Taster

=63/37

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over