rs132630300

chrX-134377619-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate 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

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001015877.2 (PHF6) was described as [Pathogenic] in ClinVar as 96222
• 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 id is 11068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF6	NM_001015877.2	c.2T>C	p.Met1?	start_lost	2/11	ENST00000370803.8
PHF6	NM_032458.3	c.2T>C	p.Met1?	start_lost	2/10
PHF6	NM_032335.3	c.2T>C	p.Met1?	start_lost	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF6	ENST00000370803.8	c.2T>C	p.Met1?	start_lost	2/11	1	NM_001015877.2	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Borjeson-Forssman-Lehmann syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 23, 2019	For these reasons, this variant has been classified as Pathogenic. 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 variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the PHF6 mRNA. The next in-frame methionine is located at codon 46. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Aug 12, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Wales Gene Park, Division Of Cancer and Genetics, Cardiff University	May 12, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 22, 2022

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

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Dec 22, 2021

PVS1, PM2, PP3, PP5 -

Computational scores

Source: dbNSFP v4.3

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;T;T;.;.
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
PROVEAN	Benign	-1.3	N;N;.;N;N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.93	P;P;.;.;D
Vest4		0.94
MutPred		0.99		Gain of glycosylation at M1 (P = 0.0135);Gain of glycosylation at M1 (P = 0.0135);Gain of glycosylation at M1 (P = 0.0135);Gain of glycosylation at M1 (P = 0.0135);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

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: rs132630300; hg19: chrX-133511649;