rs727503377

Variant names:

• chrX-83509406-TCTGA-T
• rs727503377
• NM_000307.5:c.1086_*3delACTG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM2 PM4 PP5_Moderate

The NM_000307.5(POU3F4):​c.1086_*3delACTG​(p.Ter362TrpfsTer106) 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 (★). ClinVar reports functional evidence for this variant: "SCV000199953: Functional analyses reveal that these variants alter the protein?s expression, localization and function (Choi 2013)".

• 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
• Publications: 0 publications found

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]

POU3F4 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked mixed hearing loss with perilymphatic gusher

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial non-syndromic sensorineural hearing loss

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• choroideremia-deafness-obesity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307072 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000199953: Functional analyses reveal that these variants alter the protein?s expression, localization and function (Choi 2013)
• 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 VariationId is 164976.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000307.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F4	NM_000307.5	MANE Select	c.1086_*3delACTG	p.Ter362TrpfsTer106	frameshift stop_lost	Exon 1 of 1	NP_000298.3	A0A2R8Y739
	POU3F4	NM_000307.5	MANE Select	c.1086_*3delACTG		3_prime_UTR	Exon 1 of 1	NP_000298.3	A0A2R8Y739

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F4	ENST00000644024.2	MANE Select	c.1086_*3delACTG	p.Ter362TrpfsTer106	frameshift stop_lost	Exon 1 of 1	ENSP00000495996.1	A0A2R8Y739
	POU3F4	ENST00000644024.2	MANE Select	c.1086_*3delACTG		3_prime_UTR	Exon 1 of 1	ENSP00000495996.1	A0A2R8Y739
	ENSG00000307072	ENST00000823276.1		n.183-109_183-106delTCAG		intron	N/A

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0

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

Other links and lift over

dbSNP: rs727503377; hg19: chrX-82764414;