rs1553426462

Variant names:

• chr2-104856495-TTCAAGCAGCGGCGCA-T
• rs1553426462
• NM_006236.3:c.992_1006delAGCGGCGCATCAAGC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM4 PP3 PP5_Moderate

The NM_006236.3(POU3F3):​c.992_1006delAGCGGCGCATCAAGC​(p.Gln331_Lys335del) variant causes a disruptive inframe deletion 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 DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POU3F3 NM_006236.3 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.60
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a domain POU-specific (size 74) in uniprot entity PO3F3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_006236.3
• PM4: Nonframeshift variant in NON repetitive region in NM_006236.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 2-104856495-TTCAAGCAGCGGCGCA-T is Pathogenic according to our data. Variant chr2-104856495-TTCAAGCAGCGGCGCA-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520803.Status of the report is criteria_provided_single_submitter, 1 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.992_1006delAGCGGCGCATCAAGC	p.Gln331_Lys335del	disruptive_inframe_deletion	Exon 1 of 1	NP_006227.1	P20264
	POU3F3	NM_001433704.1		c.992_1006delAGCGGCGCATCAAGC	p.Gln331_Lys335del	disruptive_inframe_deletion	Exon 2 of 2	NP_001420633.1	P20264
	POU3F3	NR_197431.1		n.294+2933_294+2947delAGCGGCGCATCAAGC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F3	ENST00000361360.4	TSL:6 MANE Select	c.992_1006delAGCGGCGCATCAAGC	p.Gln331_Lys335del	disruptive_inframe_deletion	Exon 1 of 1	ENSP00000355001.2	P20264
	POU3F3	ENST00000674056.1		c.992_1006delAGCGGCGCATCAAGC	p.Gln331_Lys335del	disruptive_inframe_deletion	Exon 4 of 4	ENSP00000501036.1	P20264
	ENSG00000269707	ENST00000598623.1	TSL:5	n.345+2670_345+2684delAGCGGCGCATCAAGC		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6
Mutation Taster		=14/186	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553426462; hg19: chr2-105472953;