rs142630105

Variant names:

• chrX-53940446-C-A
• rs142630105
• NM_015107.3:c.2720G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-53940446-C-A
• chrX-53940446-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015107.3(PHF8):​c.2720G>T​(p.Arg907Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,094,843 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R907H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: PHF8 NM_015107.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• Publications: 7 publications found

Genes affected

PHF8 (HGNC:20672): (PHD finger protein 8) The protein encoded by this gene is a histone lysine demethylase that preferentially acts on histones in the monomethyl or dimethyl states. The encoded protein requires Fe(2+) ion, 2-oxoglutarate, and oxygen for its catalytic activity. The protein has an N-terminal PHD finger and a central Jumonji C domain. This gene is thought to function as a transcription activator. Defects in this gene are a cause of syndromic X-linked Siderius type intellectual disability (MRXSSD) and over-expression of this gene is associated with several forms of cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

PHF8 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability Siderius type

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08071363).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015107.3. 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
	PHF8	NM_015107.3	MANE Select	c.2720G>T	p.Arg907Leu	missense	Exon 21 of 22	NP_055922.1	Q9UPP1-2
	PHF8	NM_001184896.1		c.2828G>T	p.Arg943Leu	missense	Exon 21 of 22	NP_001171825.1	Q9UPP1-1
	PHF8	NM_001441096.1		c.2525G>T	p.Arg842Leu	missense	Exon 20 of 22	NP_001428025.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF8	ENST00000338154.11	TSL:1 MANE Select	c.2720G>T	p.Arg907Leu	missense	Exon 21 of 22	ENSP00000338868.6	Q9UPP1-2
	PHF8	ENST00000357988.9	TSL:1	c.2828G>T	p.Arg943Leu	missense	Exon 21 of 22	ENSP00000350676.5	Q9UPP1-1
	PHF8	ENST00000396282.7	TSL:5	c.2720G>T	p.Arg907Leu	missense	Exon 20 of 22	ENSP00000379578.3	H0Y3N9

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000553 AC: 1 AN: 180726 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1094843 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 360293

African (AFR) AF: 0.00 AC: 0 AN: 26334

American (AMR) AF: 0.0000285 AC: 1 AN: 35134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19347

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 53879

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40489

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4117

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839382

Other (OTH) AF: 0.00 AC: 0 AN: 45982

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.76	N
PhyloP100		0.31
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.060
Sift	Benign	0.29	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.16		Loss of MoRF binding (P = 0.0929)
MVP		0.32
MPC		1.7
ClinPred		0.19	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.37
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs142630105; hg19: chrX-53966879;