X-134377706-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001015877.2(PHF6):c.89A>G(p.Gln30Arg) 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: 23)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.87

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Extended PHD1 domain (ePHD1) (size 118) in uniprot entity PHF6_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001015877.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF6	NM_001015877.2	c.89A>G	p.Gln30Arg	missense_variant	2/11	ENST00000370803.8
PHF6	NM_032458.3	c.89A>G	p.Gln30Arg	missense_variant	2/10
PHF6	NM_032335.3	c.89A>G	p.Gln30Arg	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF6	ENST00000370803.8	c.89A>G	p.Gln30Arg	missense_variant	2/11	1	NM_001015877.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

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

Invitae

Jun 28, 2022

This variant is not present in population databases (gnomAD no frequency). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). This variant has not been reported in the literature in individuals affected with PHF6-related conditions. This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 30 of the PHF6 protein (p.Gln30Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Benign	20
Dann	Benign	0.95
DEOGEN2	Benign	0.098	T;T;T;.;.
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.0	L;L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.84	N;N;.;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.62	T;T;.;T;T
Sift4G	Benign	0.83	T;T;T;T;T
Polyphen		0.017	B;B;.;.;P
Vest4		0.80
MutPred		0.27		Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);Gain of MoRF binding (P = 0.0203);
MVP		1.0
MPC		1.2
ClinPred		0.72	D
GERP RS		5.8
Varity_R		0.57
gMVP		0.85

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: rs2077284380; hg19: chrX-133511736;