NM_000307.5:c.655C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000307.5(POU3F4):c.655C>T(p.Leu219Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,210,905 control chromosomes in the GnomAD database, including 1 homozygotes. There are 150 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.00025 ( 1 hom. 147 hem. )

Consequence

POU3F4
NM_000307.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.09

Publications

1 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: PanelApp Australia, 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: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant X-83508979-C-T is Benign according to our data. Variant chrX-83508979-C-T is described in ClinVar as Benign. ClinVar VariationId is 504940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.09 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 3 XL,Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F4	NM_000307.5 link	c.655C>T	p.Leu219Leu	synonymous_variant	Exon 1 of 1	ENST00000644024.2	NP_000298.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
POU3F4	ENST00000644024.2 link	c.655C>T	p.Leu219Leu	synonymous_variant	Exon 1 of 1		NM_000307.5	ENSP00000495996.1
ENSG00000279437	ENST00000625081.1 link	n.236G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000307072	ENST00000823276.1 link	n.505G>A		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000307072	ENST00000823277.1 link	n.452G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000888

AC:

AN:

112606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00295

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000469

AC:

AN:

183446

AF XY:

0.000707

show subpopulations

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:

0.0000366

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000246

AC:

270

AN:

1098245

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

147

AN XY:

363599

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00430

AC:

233

AN:

54149

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000273

AC:

AN:

842127

Other (OTH)

AF:

0.000174

AC:

AN:

46097

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

AF:

0.0000799

AC:

AN:

112660

Hom.:

Cov.:

AF XY:

0.0000862

AC XY:

AN XY:

34802

show subpopulations

African (AFR)

AF:

0.0000322

AC:

AN:

31072

American (AMR)

AF:

0.00

AC:

AN:

10756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3550

South Asian (SAS)

AF:

0.00258

AC:

AN:

2709

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53305

Other (OTH)

AF:

0.00

AC:

AN:

1538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 28, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 05, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Leu219Leu in exon 1 of POU3F4: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.5% (47/10079) o f South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs781092151). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

2.1

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over