dbSNP rs1553426334: POU3F3:p.Pro102His (chr2-104855815-C-A) – 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>A(p.Pro102His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000961 in 1,041,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P102L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 9.6e-7 ( 0 hom. )

Consequence

POU3F3
NM_006236.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

Genome browser will be placed here

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=0.3474422).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F3	NM_006236.3 link	c.305C>A	p.Pro102His	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>A	p.Pro102His	missense_variant	Exon 1 of 1	6	NM_006236.3	ENSP00000355001.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.61e-7

AC:

AN:

1041102

Hom.:

Cov.:

AF XY:

0.00000196

AC XY:

AN XY:

509578

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:

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:

0.0000237

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:

886736

Other (OTH)

AF:

0.00

AC:

AN:

36752

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Pathogenic

0.96

BayesDel_addAF

Benign

-0.0075

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.15

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.77

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.35

MetaSVM

Uncertain

-0.055

MutationAssessor

Benign

1.1

PhyloP100

3.2

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.87

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.27

MutPred

0.31

Loss of glycosylation at P102 (P = 0.0214);

MVP

0.70

ClinPred

0.84

GERP RS

0.57

Varity_R

0.42

gMVP

0.24

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

Computational scores

Splicing

Publications

Other links and lift over