rs132630300

Variant names:

• chrX-134377619-T-C
• rs132630300
• NM_001015877.2:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001015877.2(PHF6):​c.2T>C​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHF6 NM_001015877.2 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.42
• Publications: 6 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 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 11 pathogenic variants. Next in-frame start position is after 46 codons. Genomic position: 134377753. Lost 0.124 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-134377619-T-C is Pathogenic according to our data. Variant chrX-134377619-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001015877.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF6	NM_001015877.2	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	NP_001015877.1
	PHF6	NM_032458.3		c.2T>C	p.Met1?	start_lost	Exon 2 of 10	NP_115834.1
	PHF6	NM_032335.3		c.2T>C	p.Met1?	start_lost	Exon 2 of 8	NP_115711.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF6	ENST00000370803.8	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 2 of 11	ENSP00000359839.4
	PHF6	ENST00000332070.7	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 2 of 10	ENSP00000329097.3
	PHF6	ENST00000370799.5	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 2 of 9	ENSP00000359835.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

Alfa AF: 0.0000662 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Borjeson-Forssman-Lehmann syndrome Pathogenic:5

Aug 12, 2019

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 23, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed to segregate with Börjeson–Forssman–Lehmann syndrome in several families (PMID: 12415272, 15994862, Invitae). ClinVar contains an entry for this variant (Variation ID: 11068). This sequence change affects the initiator methionine of the PHF6 mRNA. The next in-frame methionine is located at codon 46. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic.

May 12, 2023

Wales Gene Park, Division Of Cancer and Genetics, Cardiff University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:1

Jul 22, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12415272)

Hereditary spastic paraplegia 4 Pathogenic:1

Dec 22, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP3, PP5

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.61
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.81	D
PhyloP100		7.4
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.93	P
Vest4		0.94
MutPred		0.99		Gain of glycosylation at M1 (P = 0.0135)
MVP		1.0
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.76
Mutation Taster		=2/198	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: rs132630300; hg19: chrX-133511649;