NM_001015877.2:c.44G>A

Variant names:

• chrX-134377661-G-A
• rs1302895379
• NM_001015877.2:c.44G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001015877.2(PHF6):​c.44G>A​(p.Arg15His) variant causes a missense change. The variant allele was found at a frequency of 0.00000579 in 1,208,187 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35705367).

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.44G>A	p.Arg15His	missense	Exon 2 of 11	NP_001015877.1	Q8IWS0-1
	PHF6	NM_032458.3		c.44G>A	p.Arg15His	missense	Exon 2 of 10	NP_115834.1	Q8IWS0-1
	PHF6	NM_032335.3		c.44G>A	p.Arg15His	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.44G>A	p.Arg15His	missense	Exon 2 of 11	ENSP00000359839.4	Q8IWS0-1
	PHF6	ENST00000332070.7	TSL:1	c.44G>A	p.Arg15His	missense	Exon 2 of 10	ENSP00000329097.3	Q8IWS0-1
	PHF6	ENST00000370799.5	TSL:1	c.44G>A	p.Arg15His	missense	Exon 2 of 9	ENSP00000359835.1	Q5JRC6

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111060 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097127 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362537

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.0000284 AC: 1 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 841153

Other (OTH) AF: 0.00 AC: 0 AN: 46068

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111060 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33290

African (AFR) AF: 0.00 AC: 0 AN: 30576

American (AMR) AF: 0.00 AC: 0 AN: 10380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2683

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5767

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53000

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Borjeson-Forssman-Lehmann syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	0.46	N
PhyloP100		4.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.023	D
Polyphen		0.93	P
Vest4		0.36
MutPred		0.45		Loss of MoRF binding (P = 0.0361)
MVP		0.96
MPC		1.3
ClinPred		0.82	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.66
Mutation Taster		=63/37	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: rs1302895379; hg19: chrX-133511691; COSMIC: COSV100136577;