rs727503377

Positions:

• chrX-83509406-TCTGA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_000307.5(POU3F4):​c.1086_*3del variant causes a frameshift, stop lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: POU3F4 NM_000307.5 frameshift, stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.02

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000307.5 Downstream stopcodon found after 51 codons.
• PP5: Variant X-83509406-TCTGA-T is Pathogenic according to our data. Variant chrX-83509406-TCTGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-83509406-TCTGA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU3F4	NM_000307.5	c.1086_*3del		frameshift_variant, stop_lost	1/1	ENST00000644024.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU3F4	ENST00000644024.2	c.1086_*3del		frameshift_variant, stop_lost	1/1		NM_000307.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 27, 2013

The X362fs variant in POU3F4 has not been previously reported in individuals wit h hearing loss or in large population studies. This nonstop extension variant al ters the normal stop codon at position 362 leading to the addition of 106 amino acids and significant loss of the 3? untranslated region (3'UTR). Two similar ex tension variants in POU3F4, that also cause disruption of the stop codon and los s of the 3?UTR, have been reported in two individuals with hearing loss (Choi 20 13). Functional analyses reveal that these variants alter the protein?s expressi on, localization and function (Choi 2013); however, functional studies are neede d to determine whether the variant in this individual would have the same impact on the protein. In summary, this variant is likely to be pathogenic, though add itional studies are required to fully establish its clinical significance. -

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: rs727503377; hg19: chrX-82764414;