Variant 2-104855585-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006236.3(POU3F3):c.75C>G(p.Asp25Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 119,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 21)

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: 2.27

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07059693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU3F3	NM_006236.3 linkuse as main transcript	c.75C>G	p.Asp25Glu	missense_variant	1/1	ENST00000361360.4	NP_006227.1	P20264

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU3F3	ENST00000361360.4 linkuse as main transcript	c.75C>G	p.Asp25Glu	missense_variant	1/1	6	NM_006236.3	ENSP00000355001.2		P20264

Frequencies

GnomAD3 genomes

AF:

0.0000167

AC:

AN:

119830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000620

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

863028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

405082

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000167

AC:

AN:

119830

Hom.:

Cov.:

AF XY:

0.0000348

AC XY:

AN XY:

57424

show subpopulations

Gnomad4 AFR

AF:

0.0000620

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

The c.75C>G (p.D25E) alteration is located in exon 1 (coding exon 1) of the POU3F3 gene. This alteration results from a C to G substitution at nucleotide position 75, causing the aspartic acid (D) at amino acid position 25 to be replaced by a glutamic acid (E). Based on data from gnomAD, the G allele has an overall frequency of 0.005% (1/19992) total alleles studied. The highest observed frequency was 0.015% (1/6690) of African alleles. This amino acid position is conserved in available vertebrate species with limited sequence alignment. This 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

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.70

DEOGEN2

Benign

0.074

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.32

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.66

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.0

REVEL

Benign

0.24

Sift

Benign

0.66

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.089

MutPred

0.37

Gain of loop (P = 0.2045);

MVP

0.16

ClinPred

0.037

GERP RS

-2.2

Varity_R

0.048

gMVP

0.14

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over