X-134377638-GA-G

Position:

• chrX-134377638-GA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001015877.2(PHF6):​c.27delA​(p.Pro11fs) variant causes a frameshift 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHF6 NM_001015877.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.83

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]

PHF6 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.975 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-134377638-GA-G is Pathogenic according to our data. Variant chrX-134377638-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 981735.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHF6	NM_001015877.2	c.27delA	p.Pro11fs	frameshift_variant	2/11	ENST00000370803.8	NP_001015877.1
PHF6	NM_032458.3	c.27delA	p.Pro11fs	frameshift_variant	2/10		NP_115834.1
PHF6	NM_032335.3	c.27delA	p.Pro11fs	frameshift_variant	2/8		NP_115711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHF6	ENST00000370803.8	c.27delA	p.Pro11fs	frameshift_variant	2/11	1	NM_001015877.2	ENSP00000359839.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hirsutism;C3714756:Intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Autoinflammatory diseases unit, CHU de Montpellier

Dec 03, 2018

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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: rs758791658; hg19: chrX-133511668;