chr2-104855815-C-A

Variant names:

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:

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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=0.3474422).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006236.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POU3F3	NM_006236.3	MANE Select	c.305C>A	p.Pro102His	missense	Exon 1 of 1	NP_006227.1
POU3F3	NM_001433704.1		c.305C>A	p.Pro102His	missense	Exon 2 of 2	NP_001420633.1
POU3F3	NR_197431.1		n.294+2246C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POU3F3	ENST00000361360.4	TSL:6 MANE Select	c.305C>A	p.Pro102His	missense	Exon 1 of 1	ENSP00000355001.2
POU3F3	ENST00000674056.1		c.305C>A	p.Pro102His	missense	Exon 4 of 4	ENSP00000501036.1
ENSG00000269707	ENST00000598623.1	TSL:5	n.345+1983C>A		intron	N/A

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 v4.9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over