Genetic Variant POU3F3:p.Gly41del (chr2-104855612-TGGC-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006236.3(POU3F3):c.120_122delCGG(p.Gly41del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00625 in 567,264 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G40G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0065 ( 0 hom. )

Consequence

POU3F3
NM_006236.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.41

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 21 AD gene.

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.120_122delCGG	p.Gly41del	disruptive_inframe_deletion	Exon 1 of 1	NP_006227.1	P20264
POU3F3	NM_001433704.1		c.120_122delCGG	p.Gly41del	disruptive_inframe_deletion	Exon 2 of 2	NP_001420633.1	P20264
POU3F3	NR_197431.1		n.294+2061_294+2063delCGG		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POU3F3	ENST00000361360.4	TSL:6 MANE Select	c.120_122delCGG	p.Gly41del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000355001.2	P20264
POU3F3	ENST00000674056.1		c.120_122delCGG	p.Gly41del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000501036.1	P20264
ENSG00000269707	ENST00000598623.1	TSL:5	n.345+1798_345+1800delCGG		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000884

AC:

AN:

23750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000616

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000892

Gnomad ASJ

AF:

0.00639

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000962

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

372

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00649

AC:

3526

AN:

543490

Hom.:

AF XY:

0.00648

AC XY:

1636

AN XY:

252534

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00658

AC:

AN:

10178

American (AMR)

AF:

0.00439

AC:

AN:

684

Ashkenazi Jewish (ASJ)

AF:

0.00823

AC:

AN:

3402

East Asian (EAS)

AF:

0.00996

AC:

AN:

2510

South Asian (SAS)

AF:

0.00530

AC:

AN:

11518

European-Finnish (FIN)

AF:

0.0135

AC:

AN:

296

Middle Eastern (MID)

AF:

0.00388

AC:

AN:

1030

European-Non Finnish (NFE)

AF:

0.00646

AC:

3206

AN:

495940

Other (OTH)

AF:

0.00714

AC:

128

AN:

17932

⚠️ 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: 0.256

Heterozygous variant carriers

545

1089

1634

2178

2723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

168

336

504

672

840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000883

AC:

AN:

23774

Hom.:

Cov.:

AF XY:

0.000840

AC XY:

AN XY:

11902

show subpopulations

African (AFR)

AF:

0.000614

AC:

AN:

6516

American (AMR)

AF:

0.000890

AC:

AN:

2246

Ashkenazi Jewish (ASJ)

AF:

0.00639

AC:

AN:

626

East Asian (EAS)

AF:

0.00

AC:

AN:

996

South Asian (SAS)

AF:

0.00

AC:

AN:

696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

760

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000962

AC:

AN:

11434

Other (OTH)

AF:

0.00

AC:

AN:

352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=88/12

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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2-104855612-TGGCGGCGGCGGCGGC-TGGCGGCGGCGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over