X-134377703-G-C

Position:

• chrX-134377703-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001015877.2(PHF6):​c.86G>C​(p.Gly29Ala) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHF6	NM_001015877.2	c.86G>C	p.Gly29Ala	missense_variant	2/11	ENST00000370803.8	NP_001015877.1
PHF6	NM_032458.3	c.86G>C	p.Gly29Ala	missense_variant	2/10		NP_115834.1
PHF6	NM_032335.3	c.86G>C	p.Gly29Ala	missense_variant	2/8		NP_115711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHF6	ENST00000370803.8	c.86G>C	p.Gly29Ala	missense_variant	2/11	1	NM_001015877.2	ENSP00000359839.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Borjeson-Forssman-Lehmann syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of Borjeson-Forssman-Lehmann syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with alanine at codon 29 of the PHF6 protein (p.Gly29Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.1	L;L;.;.;L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.4	N;N;.;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.14	T;T;.;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.71
MutPred		0.50		Loss of methylation at K26 (P = 0.1098);Loss of methylation at K26 (P = 0.1098);Loss of methylation at K26 (P = 0.1098);Loss of methylation at K26 (P = 0.1098);Loss of methylation at K26 (P = 0.1098);
MVP		0.91
MPC		2.3
ClinPred		0.85	D
GERP RS		5.8
Varity_R		0.51
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2077284343; hg19: chrX-133511733;