rs727503376

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000307.5(POU3F4):c.483C>A(p.Ser161Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000581 in 1,205,019 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000046 ( 0 hom. 3 hem. )

Consequence

POU3F4
NM_000307.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.35

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16076839).

BS2

High Hemizygotes in GnomAdExome4 at 3 XL,Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F4	NM_000307.5 link	c.483C>A	p.Ser161Arg	missense_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.483C>A	p.Ser161Arg	missense_variant	Exon 1 of 1		NM_000307.5	ENSP00000495996.1
ENSG00000279437	ENST00000625081.1 link	n.408G>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
ENSG00000307072	ENST00000823276.1 link	n.677G>T		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000307072	ENST00000823277.1 link	n.624G>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112673

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000610

AC:

AN:

163989

AF XY:

0.00

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:

0.0000692

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000458

AC:

AN:

1092346

Hom.:

Cov.:

AF XY:

0.00000837

AC XY:

AN XY:

358634

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26301

American (AMR)

AF:

0.00

AC:

AN:

34431

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19268

East Asian (EAS)

AF:

0.00

AC:

AN:

29947

South Asian (SAS)

AF:

0.00

AC:

AN:

53223

European-Finnish (FIN)

AF:

0.0000250

AC:

AN:

40062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.00000358

AC:

AN:

839077

Other (OTH)

AF:

0.0000218

AC:

AN:

45909

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112673

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34807

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31017

American (AMR)

AF:

0.00

AC:

AN:

10763

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00

AC:

AN:

2729

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6215

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53291

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Ser161Arg variant in POU3F4 has not been previously reported in individuals with hearing loss. Data from large population studies are insufficient to assess the frequency of this variant. 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 Ser161Arg variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.91

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

.;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-0.44

PhyloP100

2.3

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.58

N;.

REVEL

Uncertain

0.32

Sift

Benign

0.10

T;.

Sift4G

Benign

0.51

T;.

Vest4

0.069

MutPred

0.22

Gain of catalytic residue at S161 (P = 0.0069);Gain of catalytic residue at S161 (P = 0.0069);

MVP

0.84

MPC

1.2

ClinPred

0.22

GERP RS

4.4

gMVP

0.63

Mutation Taster

=77/23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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