rs1556019105

Variant names:

• chrX-134415042-CACA-C
• rs1556019105
• NM_001015877.2:c.763_765delACA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001015877.2(PHF6):​c.763_765delACA​(p.Thr255del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHF6 NM_001015877.2 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 8.87

Genes affected

PHF6 (HGNC:18145): (PHD finger protein 6) This gene is a member of the plant homeodomain (PHD)-like finger (PHF) family. It encodes a protein with two PHD-type zinc finger domains, indicating a potential role in transcriptional regulation, that localizes to the nucleolus. Mutations affecting the coding region of this gene or the splicing of the transcript have been associated with Borjeson-Forssman-Lehmann syndrome (BFLS), a disorder characterized by cognitive disability, epilepsy, hypogonadism, hypometabolism, obesity, swelling of subcutaneous tissue of the face, narrow palpebral fissures, and large ears. Alternate splicing results in multiple transcript variants, encoding different isoforms. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001015877.2. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF6	NM_001015877.2	c.763_765delACA	p.Thr255del	conservative_inframe_deletion	Exon 8 of 11	ENST00000370803.8	NP_001015877.1
PHF6	NM_032458.3	c.763_765delACA	p.Thr255del	conservative_inframe_deletion	Exon 8 of 10		NP_115834.1
PHF6	NM_032335.3	c.766_768delACA	p.Thr256del	conservative_inframe_deletion	Exon 8 of 8		NP_115711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF6	ENST00000370803.8	c.763_765delACA	p.Thr255del	conservative_inframe_deletion	Exon 8 of 11	1	NM_001015877.2	ENSP00000359839.4

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Borjeson-Forssman-Lehmann syndrome Pathogenic:1 Uncertain:1

Mar 14, 2024

Tgen's Center For Rare Childhood Disorders, Translational Genomics Research Institute (TGEN)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Reported as a de novo variant with confirmed parentage in a patient in the published literature; however, clinical information was not provided (PMID: 35599849). Not observed at significant frequency in large population cohorts (gnomAD). In-frame deletion of 1 amino acids in a non-repeat region. In silico analysis supports a deleterious effect on protein structure/function. -

Mar 02, 2016

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1

Mar 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a de novo variant with confirmed parentage in a patient in the published literature; however, clinical information was not provided (PMID: 35599849); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35599849) -

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: rs1556019105; hg19: chrX-133549072;