chrX-83508424-C-CCTCA

Position:

• chrX-83508424-C-CCTCA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000307.5(POU3F4):​c.101_104dup​(p.Gln35HisfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: POU3F4 NM_000307.5 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.06

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 Likely_pathogenic. Variant got 7 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-83508424-C-CCTCA is Pathogenic according to our data. Variant chrX-83508424-C-CCTCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3256914.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU3F4	NM_000307.5	c.101_104dup	p.Gln35HisfsTer8	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.101_104dup	p.Gln35HisfsTer8	frameshift_variant	1/1		NM_000307.5	ENSP00000495996	P1
	ENST00000625081.1	n.790_791insTGAG		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Likely pathogenic, no assertion criteria provided

research

Kunming Children's Hospital, Yunnan Key Laboratory of Children’s Major Disease Research

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According to the ACMG guidelines, this variant is classified as a frameshift mutation (zero-effect variant) that potentially leads to loss of gene function (PVS1). In the normal population databases, such as 1000 Genomes database (http://www.1000genomes.org/), GnomAD database (http://gnomad.broadinstitute.org/downloads), EXAC database (http://exac.broadinstitute.org/), mutation frequency was not observed, indicating it’s a low-frequency mutation (PM2). This evidence satisfies both PVS1 and PM2 criteria, supporting the preliminary assessment of this variant as a likely pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-82763432;