rs397516336

Positions:

• chrX-83509176-CAT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000307.5(POU3F4):​c.853_854delAT​(p.Ile285fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: POU3F4 NM_000307.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.29

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 Likely_pathogenic. Variant got 8 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-83509176-CAT-C is Pathogenic according to our data. Variant chrX-83509176-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 43352.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-83509176-CAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU3F4	NM_000307.5	c.853_854delAT	p.Ile285fs	frameshift_variant	1/1	ENST00000644024.2	NP_000298.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU3F4	ENST00000644024.2	c.853_854delAT	p.Ile285fs	frameshift_variant	1/1		NM_000307.5	ENSP00000495996.1
ENSG00000279437	ENST00000625081.1	n.37_38delAT		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 24

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked mixed hearing loss with perilymphatic gusher Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Prof. Karen Avraham, Tel Aviv University

May 07, 2018

X-linked, congenital, profound NSHL; Mondini -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 18, 2012

The Ile285fs variant in POU3F4 has not been reported in the literature nor previ ously identified by our laboratory. However, this frameshift variant is predicte d to alter the protein?s amino acid sequence beginning at position 285 and lead to a premature termination codon 43 amino acids downstream. This alteration is t hen predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LM M). -

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: rs397516336; hg19: chrX-82764184;