NM_001015877.2:c.119C>A

Variant names:

• chrX-134377736-C-A
• rs1556013242
• NM_001015877.2:c.119C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001015877.2(PHF6):​c.119C>A​(p.Ala40Glu) 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 other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A40T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 7.50
• Publications: 0 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), Genomics England PanelApp, ClinGen, Illumina, G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001015877.2
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001015877.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF6	NM_001015877.2	MANE Select	c.119C>A	p.Ala40Glu	missense	Exon 2 of 11	NP_001015877.1	Q8IWS0-1
	PHF6	NM_032458.3		c.119C>A	p.Ala40Glu	missense	Exon 2 of 10	NP_115834.1	Q8IWS0-1
	PHF6	NM_032335.3		c.119C>A	p.Ala40Glu	missense	Exon 2 of 8	NP_115711.2	Q8IWS0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF6	ENST00000370803.8	TSL:1 MANE Select	c.119C>A	p.Ala40Glu	missense	Exon 2 of 11	ENSP00000359839.4	Q8IWS0-1
	PHF6	ENST00000332070.7	TSL:1	c.119C>A	p.Ala40Glu	missense	Exon 2 of 10	ENSP00000329097.3	Q8IWS0-1
	PHF6	ENST00000370799.5	TSL:1	c.119C>A	p.Ala40Glu	missense	Exon 2 of 9	ENSP00000359835.1	Q5JRC6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: other

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Neuroblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.1	L
PhyloP100		7.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.71		Gain of disorder (P = 0.0324)
MVP		0.98
MPC		2.4
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.98
Mutation Taster		=15/85	disease causing

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: rs1556013242; hg19: chrX-133511766;