Genetic Variant POU3F3:p.Gly42AlafsTer17 (chr2-104855628-GGCG-GGC) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006236.3(POU3F3):c.125delG(p.Gly42AlafsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

POU3F3
NM_006236.3 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.65

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: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 50 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-104855628-GGCG-GGC is Pathogenic according to our data. Variant chr2-104855630-CG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 985404.Status of the report is criteria_provided_single_submitter, 1 stars.

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.125delG	p.Gly42AlafsTer17	frameshift	Exon 1 of 1	NP_006227.1	P20264
POU3F3	NM_001433704.1		c.125delG	p.Gly42AlafsTer17	frameshift	Exon 2 of 2	NP_001420633.1	P20264
POU3F3	NR_197431.1		n.294+2066delG		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POU3F3	ENST00000361360.4	TSL:6 MANE Select	c.125delG	p.Gly42AlafsTer17	frameshift	Exon 1 of 1	ENSP00000355001.2	P20264
POU3F3	ENST00000674056.1		c.125delG	p.Gly42AlafsTer17	frameshift	Exon 4 of 4	ENSP00000501036.1	P20264
ENSG00000269707	ENST00000598623.1	TSL:5	n.345+1803delG		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

291536

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

135226

African (AFR)

AF:

0.00

AC:

AN:

5750

American (AMR)

AF:

0.00

AC:

AN:

430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1804

East Asian (EAS)

AF:

0.00

AC:

AN:

1462

South Asian (SAS)

AF:

0.00

AC:

AN:

6156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

554

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

265684

Other (OTH)

AF:

0.00

AC:

AN:

9542

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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chr2-104855630-CGGG-C

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