chrX-83508463-C-T

Position:

chrX-83508463-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000307.5(POU3F4):c.139C>T(p.Pro47Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00027 in 1,208,648 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 26 hem., cov: 23)

Exomes 𝑓: 0.00019 ( 0 hom. 76 hem. )

Consequence

POU3F4
NM_000307.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.87

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008189499).

BP6

Variant X-83508463-C-T is Benign according to our data. Variant chrX-83508463-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 26 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU3F4	NM_000307.5 linkuse as main transcript	c.139C>T	p.Pro47Ser	missense_variant	1/1	ENST00000644024.2	NP_000298.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU3F4	ENST00000644024.2 linkuse as main transcript	c.139C>T	p.Pro47Ser	missense_variant	1/1		NM_000307.5	ENSP00000495996	P1
	ENST00000625081.1 linkuse as main transcript	n.752G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

120

AN:

112590

Hom.:

Cov.:

AF XY:

0.000749

AC XY:

AN XY:

34734

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00103

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:

0.000113

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.000408

AC:

AN:

176341

Hom.:

AF XY:

0.000277

AC XY:

AN XY:

61441

show subpopulations

Gnomad AFR exome

AF:

0.00420

Gnomad AMR exome

AF:

0.000223

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000188

AC:

206

AN:

1096008

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

AN XY:

361540

show subpopulations

Gnomad4 AFR exome

AF:

0.00334

Gnomad4 AMR exome

AF:

0.000257

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.000391

GnomAD4 genome

AF:

0.00107

AC:

120

AN:

112640

Hom.:

Cov.:

AF XY:

0.000747

AC XY:

AN XY:

34794

show subpopulations

Gnomad4 AFR

AF:

0.00325

Gnomad4 AMR

AF:

0.00102

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.00126

ESP6500AA

AF:

0.00495

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000585

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The POU3F4 p.Pro47Ser variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs144417952) and ClinVar (classified as likely benign by Laboratory for Molecular Medicine and Illumina). The variant was also identified in control databases in 97 of 198285 chromosomes (26 hemizygous) at a frequency of 0.000489 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 76 of 18537 chromosomes (freq: 0.0041), Latino in 7 of 27514 chromosomes (freq: 0.000254) and European (non-Finnish) in 14 of 88908 chromosomes (freq: 0.000158), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Pro47 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

POU3F4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

p.Pro47Ser in Exon 1 of POU3F4: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (14/3216) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS; dbSNP rs144417952). -

X-linked mixed hearing loss with perilymphatic gusher

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.76

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.80

.;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-0.66

MutationTaster

Benign

0.95

PrimateAI

Uncertain

0.64

PROVEAN

Benign

0.51

N;.

REVEL

Benign

0.24

Sift

Benign

0.89

T;.

Sift4G

Benign

0.75

T;.

Vest4

0.33

MVP

0.78

MPC

1.0

ClinPred

0.016

GERP RS

4.3

gMVP

0.61

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over