rs876657719

Variant names:

• chrX-83508926-TCAAA-T
• rs876657719
• NM_000307.5:c.607_610delCAAA

Your query was ambiguous. Multiple possible variants found:

• chrX-83508926-TCAAA-T
• chrX-83508926-TCAAA-TCAAACAAA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000307.5(POU3F4):​c.607_610delCAAA​(p.Gln203GlufsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,255 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: POU3F4 NM_000307.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.07

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]

ENSG00000279437 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-83508926-TCAAA-T is Pathogenic according to our data. Variant chrX-83508926-TCAAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 228391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F4	NM_000307.5	c.607_610delCAAA	p.Gln203GlufsTer37	frameshift_variant	Exon 1 of 1	ENST00000644024.2	NP_000298.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU3F4	ENST00000644024.2	c.607_610delCAAA	p.Gln203GlufsTer37	frameshift_variant	Exon 1 of 1		NM_000307.5	ENSP00000495996.1
ENSG00000279437	ENST00000625081.1	n.285_288delTTTG		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098255 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 363609

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked mixed hearing loss with perilymphatic gusher Pathogenic:2

Apr 25, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2021

Neurogenetic Laboratory, Second Faculty of Medicine, Charles University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1

Mar 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gln203fs variant in POU3F4 has been reported in one individual with sensor ineural hearing loss and segregated in six affected male family members (de Kok 1995). This variant is predicted to cause a frameshift, which alters the protein ?s amino acid sequence beginning at position 203 and leads to a premature termin ation codon 37 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the POU3F4 gene is an est ablished disease mechanism in X-linked hearing loss. In summary, this variant me ets our criteria to be classified as pathogenic (www.partners.org/personalizedme dicine/lmm). -

Computational scores

Source: dbNSFP v4.3

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: rs876657719; hg19: chrX-82763934;