rs142630105

chrX-53940446-C-AchrX-53940446-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 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. 14/20 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PHF8
• BP4: Computational evidence support a benign effect (MetaRNN=0.08071363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF8	NM_015107.3	c.2720G>T	p.Arg907Leu	missense_variant	21/22	ENST00000338154.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF8	ENST00000338154.11	c.2720G>T	p.Arg907Leu	missense_variant	21/22	1	NM_015107.3	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000553 AC: 1 AN: 180726 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65360

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.081	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.68	D;D;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.73	N;N;N
REVEL	Benign	0.060
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.32	T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs142630105; hg19: chrX-53966879;