5-146339164-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_002700.3(POU4F3):c.54del(p.Glu18AspfsTer66) 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: 33)
• Consequence: POU4F3 NM_002700.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.50

Genes affected

POU4F3 (HGNC:9220): (POU class 4 homeobox 3) This gene encodes a member of the POU-domain family of transcription factors. POU-domain proteins have been observed to play important roles in control of cell identity in several systems. This protein is found in the retina and may play a role in determining or maintaining the identities of a small subset of visual system neurons. Defects in this gene are the cause of non-syndromic sensorineural deafness autosomal dominant type 15. [provided by RefSeq, Mar 2009]

LOC127814297 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-146339164-GA-G is Pathogenic according to our data. Variant chr5-146339164-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 1334107.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU4F3	NM_002700.3	c.54del	p.Glu18AspfsTer66	frameshift_variant	1/2	ENST00000646991.2
LOC127814297	NM_001414499.1	c.2887del	p.Thr963ProfsTer321	frameshift_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU4F3	ENST00000646991.2	c.54del	p.Glu18AspfsTer66	frameshift_variant	1/2		NM_002700.3	P1
	ENST00000515598.1	n.404-31889del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 15 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

King Laboratory, University of Washington

Aug 01, 2020

POU4F3 c.54delA leads to a stop at codon 84. It is homozygous in a Palestinian child with severe to profound hearing loss (Abu Rayyan 2020). The variant is absent from 1300 Palestinian controls and absent from gnomAD v2.1.1. -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-145718727;