Genetic Variant NM_000307.5:c.708G>A (chrX-83509032-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM2PP3BP6_ModerateBP7

The NM_000307.5(POU3F4):c.708G>A(p.Glu236Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,259 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

POU3F4
NM_000307.5 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.39

Publications

18 publications found

Variant links:

Genes affected

POU3F4 (HGNC:9217): (POU class 3 homeobox 4) This gene encodes a member of the POU-III class of neural transcription factors. This family member plays a role in inner ear development. The protein is thought to be involved in the mediation of epigenetic signals which induce striatal neuron-precursor differentiation. Mutations in this gene are associated with X chromosome-linked nonsyndromic mixed deafness. [provided by RefSeq, Dec 2012]

POU3F4 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
X-linked mixed hearing loss with perilymphatic gusher
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
mitochondrial non-syndromic sensorineural hearing loss
Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
choroideremia-deafness-obesity syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

POU3F4 links:

ENSG00000279437 (HGNC:):

ENSG00000279437 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

BayesDel_noAF computational evidence supports a deleterious effect, 0.2

BP6

Variant X-83509032-G-A is Benign according to our data. Variant chrX-83509032-G-A is described in ClinVar as Benign. ClinVar VariationId is 1628834.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=2.39 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000307.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F4	NM_000307.5	MANE Select	c.708G>A	p.Glu236Glu	synonymous	Exon 1 of 1	NP_000298.3	A0A2R8Y739

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POU3F4	ENST00000644024.2	MANE Select	c.708G>A	p.Glu236Glu	synonymous	Exon 1 of 1	ENSP00000495996.1	A0A2R8Y739
ENSG00000279437	ENST00000625081.1	TSL:6	n.183C>T		non_coding_transcript_exon	Exon 1 of 1
ENSG00000307072	ENST00000823276.1		n.452C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1098259

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363613

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40533

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842141

Other (OTH)

AF:

0.0000434

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Benign

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

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

PhyloP100

2.4

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over