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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F3	NM_006236.3	c.992_1006delAGCGGCGCATCAAGC	p.Gln331_Lys335del	disruptive_inframe_deletion	Exon 1 of 1	ENST00000361360.4	NP_006227.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU3F3	ENST00000361360.4	c.992_1006delAGCGGCGCATCAAGC	p.Gln331_Lys335del	disruptive_inframe_deletion	Exon 1 of 1	6	NM_006236.3	ENSP00000355001.2

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Feb 19, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The alteration results in an in-frame deletion: _x000D_ _x000D_ The c.992_1006del15 (p.Q331_K335del) alteration, located in coding exon 1 of the POU3F3 gene, results from an in-frame deletion of 15 nucleotides at positions 992 to 1006. This results in the deletion of 5 amino acids between codons 331 and 335. The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the POU3F3 c.992_1006del15 alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was confirmed de novo in a 12 year old female patient with borderline ID, delayed speech and motor development, and dysmorphic features including cupped ears, long/narrow face, full lips, and high/narrow palate (Snijders Blok, 2019). The deleted amino acids are conserved throughout evolution:_x000D_ _x000D_ The Q331_K335 amino acids are completely conserved in available vertebrate species. The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.Q331_K335del alteration is predicted to be deleterious with a score of -38.00 by PROVEAN in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;