rs1553426479

Positions:

• chr2-104856706-AG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006236.3(POU3F3):​c.1197del​(p.Ile400SerfsTer16) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: POU3F3 NM_006236.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.38

Genes affected

POU3F3 (HGNC:9216): (POU class 3 homeobox 3) This gene encodes a POU-domain containing protein that functions as a transcription factor. The encoded protein recognizes an octamer sequence in the DNA of target genes. This protein may play a role in development of the nervous system. [provided by RefSeq, Apr 2015]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-104856706-AG-A is Pathogenic according to our data. Variant chr2-104856706-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521216.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-104856706-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU3F3	NM_006236.3	c.1197del	p.Ile400SerfsTer16	frameshift_variant	1/1	ENST00000361360.4	NP_006227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU3F3	ENST00000361360.4	c.1197del	p.Ile400SerfsTer16	frameshift_variant	1/1		NM_006236.3	ENSP00000355001	P1
	ENST00000662784.1	n.166+2875del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2020

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1197delG (p.I400Sfs*16) alteration, located in coding exon 1 of the POU3F3 gene, consists of a deletion of one nucleotide at position 1197, causing a translational frameshift with a predicted alternate stop codon after 16 amino acids. Frameshifts are typically deleterious in nature; however, because POU3F3 is a single-exon gene this alteration is not expected to trigger nonsense-mediated mRNA decay and an altered protein could still be expressed (Maquat, 2004). This alteration impacts the last 101 amino acids of the protein and this region contains the C-terminal POU-homeobox domain, which is required for sequence specific DNA binding (Rosenfeld, 1991) and in vitro studies have shown that this alteration results in abnormal subcellular localization, significantly decreased transcriptional activation function, and significantly decreased dimerization (Snijders Blok, 2019). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the POU3F3 c.1197delG alteration was not observed, with coverage at this position. Based on the available evidence, this alteration is classified as likely pathogenic. -

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

LitVar

Other links and lift over

dbSNP: rs1553426479; hg19: chr2-105473164;