X-83508463-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.87

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]

(HGNC:):

ACMG classification

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 GnomAd at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU3F4	NM_000307.5	c.139C>T	p.Pro47Ser	missense_variant	1/1	ENST00000644024.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 120 AN: 112590 Hom.: 0 Cov.: 23 AF XY: 0.000749 AC XY: 26 AN XY: 34734

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: 72 AN: 176341 Hom.: 0 AF XY: 0.000277 AC XY: 17 AN XY: 61441

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.: 0 Cov.: 31 AF XY: 0.000210 AC XY: 76 AN XY: 361540

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.: 0 Cov.: 23 AF XY: 0.000747 AC XY: 26 AN XY: 34794

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.: 4

Bravo AF: 0.00126

ESP6500AA AF: 0.00495 AC: 19

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000585 AC: 71

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2019	- -
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. -

POU3F4-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Benign	0.76
FATHMM_MKL	Benign	0.62	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.64	T
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	T
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

Other links and lift over

dbSNP: rs144417952; hg19: chrX-82763471; COSMIC: COSV100937351;