rs1556013227

Variant names:

• chrX-134377688-G-C
• rs1556013227
• NM_001015877.2:c.71G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001015877.2(PHF6):​c.71G>C​(p.Arg24Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000273 in 1,097,047 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.01
• 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: Uncertain_significance. The variant received 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23678541).

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.71G>C	p.Arg24Thr	missense	Exon 2 of 11	NP_001015877.1	Q8IWS0-1
	PHF6	NM_032458.3		c.71G>C	p.Arg24Thr	missense	Exon 2 of 10	NP_115834.1	Q8IWS0-1
	PHF6	NM_032335.3		c.71G>C	p.Arg24Thr	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.71G>C	p.Arg24Thr	missense	Exon 2 of 11	ENSP00000359839.4	Q8IWS0-1
	PHF6	ENST00000332070.7	TSL:1	c.71G>C	p.Arg24Thr	missense	Exon 2 of 10	ENSP00000329097.3	Q8IWS0-1
	PHF6	ENST00000370799.5	TSL:1	c.71G>C	p.Arg24Thr	missense	Exon 2 of 9	ENSP00000359835.1	Q5JRC6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183426 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097047 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362439

African (AFR) AF: 0.00 AC: 0 AN: 26381

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30186

South Asian (SAS) AF: 0.00 AC: 0 AN: 54118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 841062

Other (OTH) AF: 0.00 AC: 0 AN: 46052

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Benign	0.97	L
PhyloP100		5.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.35
Sift	Benign	0.077	T
Sift4G	Uncertain	0.028	D
Polyphen		0.22	B
Vest4		0.43
MutPred		0.33		Loss of stability (P = 0.0184)
MVP		0.88
MPC		1.6
ClinPred		0.61	D
GERP RS		5.8
Varity_R		0.39
gMVP		0.81
Mutation Taster		=48/52	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: rs1556013227; hg19: chrX-133511718;