NM_000307.5:c.506C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000307.5(POU3F4):c.506C>T(p.Pro169Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,206,558 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P169P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 4 hem., cov: 24)

Exomes 𝑓: 0.00015 ( 0 hom. 40 hem. )

Consequence

POU3F4
NM_000307.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.77

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077652335).

BP6

Variant X-83508830-C-T is Benign according to our data. Variant chrX-83508830-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43348.

BS2

High Hemizygotes in GnomAd4 at 4 XL,Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F4	NM_000307.5 link	c.506C>T	p.Pro169Leu	missense_variant	Exon 1 of 1	ENST00000644024.2	NP_000298.3	P49335A0A2R8Y739

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
POU3F4	ENST00000644024.2 link	c.506C>T	p.Pro169Leu	missense_variant	Exon 1 of 1		NM_000307.5	ENSP00000495996.1	A0A2R8Y739
ENSG00000279437	ENST00000625081.1 link	n.385G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000307072	ENST00000823276.1 link	n.654G>A		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000307072	ENST00000823277.1 link	n.601G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.000133

AC:

AN:

112563

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00526

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:

0.000657

GnomAD2 exomes

AF:

0.000322

AC:

AN:

167897

AF XY:

0.000272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00652

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000411

Gnomad OTH exome

AF:

0.000945

GnomAD4 exome

AF:

0.000149

AC:

163

AN:

1093995

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

359899

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26330

American (AMR)

AF:

0.00

AC:

AN:

34700

Ashkenazi Jewish (ASJ)

AF:

0.00612

AC:

118

AN:

19292

East Asian (EAS)

AF:

0.00

AC:

AN:

30053

South Asian (SAS)

AF:

0.00

AC:

AN:

53419

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40215

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.0000274

AC:

AN:

839893

Other (OTH)

AF:

0.000479

AC:

AN:

45964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.000133

AC:

AN:

112563

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34711

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30962

American (AMR)

AF:

0.00

AC:

AN:

10770

Ashkenazi Jewish (ASJ)

AF:

0.00526

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3547

South Asian (SAS)

AF:

0.00

AC:

AN:

2727

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53249

Other (OTH)

AF:

0.000657

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00117

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 12, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Pro169Leu variant in POU3F4 has been identified by our laboratory in one mal e individual with hearing loss (LMM-unpublished data), but was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Pro169Leu variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Apr 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.506C>T (p.P169L) alteration is located in exon 1 (coding exon 1) of the POU3F4 gene. This alteration results from a C to T substitution at nucleotide position 506, causing the proline (P) at amino acid position 169 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Feb 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.72

.;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-0.45

PhyloP100

5.8

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.8

N;.

REVEL

Benign

0.22

Sift

Benign

0.053

T;.

Sift4G

Uncertain

0.034

D;.

Vest4

0.18

MVP

0.84

MPC

1.1

ClinPred

0.057

GERP RS

5.3

gMVP

0.63

Mutation Taster

=75/25

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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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