rs132630299

Variant names:

• chrX-134377751-G-A
• rs132630299
• NM_001015877.2:c.134G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001015877.2(PHF6):​c.134G>A​(p.Cys45Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.52
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Borjeson-Forssman-Lehmann syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001015877.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.2833 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Borjeson-Forssman-Lehmann syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-134377751-G-A is Pathogenic according to our data. Variant chrX-134377751-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF6	NM_001015877.2	c.134G>A	p.Cys45Tyr	missense_variant	Exon 2 of 11	ENST00000370803.8	NP_001015877.1
PHF6	NM_032458.3	c.134G>A	p.Cys45Tyr	missense_variant	Exon 2 of 10		NP_115834.1
PHF6	NM_032335.3	c.134G>A	p.Cys45Tyr	missense_variant	Exon 2 of 8		NP_115711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF6	ENST00000370803.8	c.134G>A	p.Cys45Tyr	missense_variant	Exon 2 of 11	1	NM_001015877.2	ENSP00000359839.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Borjeson-Forssman-Lehmann syndrome Pathogenic:2

Dec 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 21, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Borjeson-Forssman-Lehmann syndrome (BFLS; MIM#301900) in males; females heterozygous for pathogenic variants show an overlapping but distinct phenotype (PMID: 35662002). (I) 0109 - This gene is associated with X-linked recessive disease in males. Female with heterozygous variants may be affected; variant type and skewed X-inactivation may contribute to gender-specific phenotypes (PMID: 35662002). (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been observed as hemizygous and de novo in one individual with BFLS, and in several affected hemizygous males and unaffected carrier females from a large family with BFLS (PMIDs: 12415272, 15580208). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant has observed as hemizygous in at least three affected males from one family with BFLS (PMID: 15580208). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies in both patient cell lines and transfected cells show reduced PHF6 protein expression (PMIDs: 33772537, 30403997). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1

Jan 31, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12415272) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D;T;.;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;H
PhyloP100		9.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.9	D;D;.;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.95
MutPred		0.97		Loss of methylation at K44 (P = 0.0143);Loss of methylation at K44 (P = 0.0143);Loss of methylation at K44 (P = 0.0143);Loss of methylation at K44 (P = 0.0143);Loss of methylation at K44 (P = 0.0143);
MVP		0.99
MPC		2.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs132630299; hg19: chrX-133511781;