X-134377620-G-T

Position:

• chrX-134377620-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The ENST00000370803.8(PHF6):​c.3G>T​(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: 23)
• Consequence: PHF6 ENST00000370803.8 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.28

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 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000370803.8 (PHF6) was described as [Pathogenic] in ClinVar as 11068
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-134377620-G-T is Pathogenic according to our data. Variant chrX-134377620-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 96222.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-134377620-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHF6	NM_001015877.2	c.3G>T	p.Met1?	start_lost	2/11	ENST00000370803.8	NP_001015877.1
PHF6	NM_032458.3	c.3G>T	p.Met1?	start_lost	2/10		NP_115834.1
PHF6	NM_032335.3	c.3G>T	p.Met1?	start_lost	2/8		NP_115711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHF6	ENST00000370803.8	c.3G>T	p.Met1?	start_lost	2/11	1	NM_001015877.2	ENSP00000359839	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 02, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T;T;T;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Benign	-0.37	N;N;.;N;N
REVEL	Pathogenic	0.74
Sift	Uncertain	0.021	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.85	P;P;.;.;P
Vest4		0.83
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0408);Gain of catalytic residue at M1 (P = 0.0408);Gain of catalytic residue at M1 (P = 0.0408);Gain of catalytic residue at M1 (P = 0.0408);Gain of catalytic residue at M1 (P = 0.0408);
MVP		0.99
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.69
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs398124428; hg19: chrX-133511650;