rs587778604

Variant names:

• chrX-134413599-C-T
• rs587778604
• NM_001015877.2:c.527C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001015877.2(PHF6):​c.527C>T​(p.Ser176Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. S176S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.78
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Borjeson-Forssman-Lehmann syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 17 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.2833 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Borjeson-Forssman-Lehmann syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF6	NM_001015877.2	c.527C>T	p.Ser176Leu	missense_variant	Exon 6 of 11	ENST00000370803.8	NP_001015877.1
PHF6	NM_032458.3	c.527C>T	p.Ser176Leu	missense_variant	Exon 6 of 10		NP_115834.1
PHF6	NM_032335.3	c.530C>T	p.Ser177Leu	missense_variant	Exon 6 of 8		NP_115711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF6	ENST00000370803.8	c.527C>T	p.Ser176Leu	missense_variant	Exon 6 of 11	1	NM_001015877.2	ENSP00000359839.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T;T;T;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	1.6	L;L;.;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.17	N;N;.;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0090	D;D;.;D;D
Sift4G	Benign	0.18	T;T;T;T;D
Polyphen		0.084	B;B;.;.;B
Vest4		0.37
MutPred		0.30		Loss of phosphorylation at S176 (P = 0.013);Loss of phosphorylation at S176 (P = 0.013);.;.;.;
MVP		0.94
MPC		1.0
ClinPred		0.83	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.79
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs587778604; hg19: chrX-133547629;