rs398124631

Variant names:

• chr5-146340306-CGCTATCCA-C
• rs398124631
• NM_002700.3:c.882_889delTATCCAGC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002700.3(POU4F3):​c.882_889delTATCCAGC​(p.Ile295ThrfsTer5) 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 (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: 7.88
• Publications: 3 publications found

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]

POU4F3 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 15

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RBM27-POU4F3 (HGNC:58349):

ENSG00000250025 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-146340306-CGCTATCCA-C is Pathogenic according to our data. Variant chr5-146340306-CGCTATCCA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7078.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002700.3. 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
	POU4F3	NM_002700.3	MANE Select	c.882_889delTATCCAGC	p.Ile295ThrfsTer5	frameshift	Exon 2 of 2	NP_002691.1	Q15319
	RBM27-POU4F3	NM_001414499.1		c.*751_*758delTATCCAGC		3_prime_UTR	Exon 20 of 20	NP_001401428.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU4F3	ENST00000646991.2	MANE Select	c.882_889delTATCCAGC	p.Ile295ThrfsTer5	frameshift	Exon 2 of 2	ENSP00000495718.1	Q15319
	POU4F3	ENST00000914229.1		c.882_889delTATCCAGC	p.Ile295ThrfsTer5	frameshift	Exon 3 of 3	ENSP00000584288.1
	ENSG00000250025	ENST00000515598.1	TSL:3	n.404-33038_404-33031delTGGATAGC		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Autosomal dominant nonsyndromic hearing loss 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398124631;

hg19: chr5-145719869;