chr5-146339148-GC-AA

Variant names:

• chr5-146339148-GC-AA
• NM_002700.3:c.36_37delGCinsAA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_002700.3(POU4F3):​c.36_37delGCinsAA​(p.MetHis12IleAsn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POU4F3 NM_002700.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000275740 (HGNC:58349):

ENSG00000250025 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 0.60352 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss.

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.36_37delGCinsAA	p.MetHis12IleAsn	missense	N/A	NP_002691.1	Q15319
	RBM27-POU4F3	NM_001414499.1		c.2869_2870delGCinsAA	p.Ala957Lys	missense	N/A	NP_001401428.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU4F3	ENST00000646991.2	MANE Select	c.36_37delGCinsAA	p.MetHis12IleAsn	missense	N/A	ENSP00000495718.1	Q15319
	ENSG00000275740	ENST00000506502.2	TSL:5	c.2992_2993delGCinsAA	p.Ala998Lys	missense	N/A	ENSP00000475384.1	U3KPZ7
	POU4F3	ENST00000914229.1		c.36_37delGCinsAA	p.MetHis12IleAsn	missense	N/A	ENSP00000584288.1

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: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5

Splicing

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

Other links and lift over

hg19: chr5-145718711;