Genetic Variant POU3F3:p.Thr3Arg (chr2-104855518-C-G) – 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.8C>G(p.Thr3Arg) 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: 23)

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: 2.03

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=0.30223107).

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	UniProt
POU3F3	NM_006236.3	MANE Select	c.8C>G	p.Thr3Arg	missense	Exon 1 of 1	NP_006227.1	P20264
POU3F3	NM_001433704.1		c.8C>G	p.Thr3Arg	missense	Exon 2 of 2	NP_001420633.1	P20264
POU3F3	NR_197431.1		n.294+1949C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POU3F3	ENST00000361360.4	TSL:6 MANE Select	c.8C>G	p.Thr3Arg	missense	Exon 1 of 1	ENSP00000355001.2	P20264
POU3F3	ENST00000674056.1		c.8C>G	p.Thr3Arg	missense	Exon 4 of 4	ENSP00000501036.1	P20264
ENSG00000269707	ENST00000598623.1	TSL:5	n.345+1686C>G		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

879898

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

416012

African (AFR)

AF:

0.00

AC:

AN:

16538

American (AMR)

AF:

0.00

AC:

AN:

4692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7620

East Asian (EAS)

AF:

0.00

AC:

AN:

4294

South Asian (SAS)

AF:

0.00

AC:

AN:

25998

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1826

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

786882

Other (OTH)

AF:

0.00

AC:

AN:

29008

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

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.060

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.41

MutationAssessor

Benign

1.9

PhyloP100

2.0

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.91

Vest4

0.41

MutPred

0.39

Loss of glycosylation at T3 (P = 0.0083)

MVP

0.73

ClinPred

0.96

Varity_R

0.58

gMVP

0.42

Mutation Taster

=81/19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over