rs104894918

chrX-134413923-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001015877.2(PHF6):c.686A>G(p.His229Arg) variant causes a missense 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 (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.85

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Extended PHD2 domain (ePHD2) (size 121) in uniprot entity PHF6_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_001015877.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant X-134413923-A-G is Pathogenic according to our data. Variant chrX-134413923-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11067.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-134413923-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF6	NM_001015877.2	c.686A>G	p.His229Arg	missense_variant	7/11	ENST00000370803.8
PHF6	NM_032458.3	c.686A>G	p.His229Arg	missense_variant	7/10
PHF6	NM_032335.3	c.689A>G	p.His230Arg	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF6	ENST00000370803.8	c.686A>G	p.His229Arg	missense_variant	7/11	1	NM_001015877.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Borjeson-Forssman-Lehmann syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T;.;.
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	1.8	L;L;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D;D;.;N;N
REVEL	Pathogenic	0.85
Sift	Uncertain	0.028	D;D;.;D;D
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.98	D;D;.;.;D
Vest4		0.77
MutPred		0.77		Gain of MoRF binding (P = 0.012);Gain of MoRF binding (P = 0.012);.;.;.;
MVP		1.0
MPC		2.5
ClinPred		0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104894918; hg19: chrX-133547953;