5-146339148-GC-G

Position:

• chr5-146339148-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002700.3(POU4F3):​c.37del​(p.His13ThrfsTer71) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POU4F3 NM_002700.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.75

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 11 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 44 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-146339148-GC-G is Pathogenic according to our data. Variant chr5-146339148-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1699941.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU4F3	NM_002700.3	c.37del	p.His13ThrfsTer71	frameshift_variant	1/2	ENST00000646991.2
LOC127814297	NM_001414499.1	c.2870del	p.Ala957AspfsTer327	frameshift_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU4F3	ENST00000646991.2	c.37del	p.His13ThrfsTer71	frameshift_variant	1/2		NM_002700.3	P1
	ENST00000515598.1	n.404-31873del		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: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 15 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Young Lab, Memorial University

Jul 28, 2022

The c.37del variant in POU4F3 has been identified in a seven generation kindred with variable, progressive autosomal dominant hearing loss, and segregated with disease. Based on the experimental evidence, we classified POU4F3 c.37del as pathogenic, meeting both conservative (PVS1, PM2, PP1_moderate, and PP3) and less conservative (PVS1, PM2, PP1_strong, and PP3) criteria according to the American College of Medical Genetics and Genomics. -

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: chr5-145718711;