chr2-104856706-AG-A

Variant names:

• chr2-104856706-AG-A
• rs1553426479
• NM_006236.3:c.1197delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_006236.3(POU3F3):​c.1197delG​(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 (★★). ClinVar reports functional evidence for this variant: "SCV000741706: "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)."" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: POU3F3 NM_006236.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.38
• Publications: 1 publications found

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]

ENSG00000269707 (HGNC:):

PANTR1 (HGNC:49513): (POU3F3 adjacent non-coding transcript 1) Predicted to act upstream of or within regulation of gene expression. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 16 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000741706: "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)."; SCV006553715: Published functional studies suggest a damaging effect with impaired subcellualar localization, transactivation activity, and dimerization capacity (PMID: 31303265)
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 521216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006236.3. 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
	POU3F3	NM_006236.3	MANE Select	c.1197delG	p.Ile400SerfsTer16	frameshift	Exon 1 of 1	NP_006227.1	P20264
	POU3F3	NM_001433704.1		c.1197delG	p.Ile400SerfsTer16	frameshift	Exon 2 of 2	NP_001420633.1	P20264
	POU3F3	NR_197431.1		n.294+3138delG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F3	ENST00000361360.4	TSL:6 MANE Select	c.1197delG	p.Ile400SerfsTer16	frameshift	Exon 1 of 1	ENSP00000355001.2	P20264
	POU3F3	ENST00000674056.1		c.1197delG	p.Ile400SerfsTer16	frameshift	Exon 4 of 4	ENSP00000501036.1	P20264
	ENSG00000269707	ENST00000598623.1	TSL:5	n.345+2875delG		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4

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

Other links and lift over

dbSNP: rs1553426479; hg19: chr2-105473164;