X-53985099-C-G

Variant names:

• chrX-53985099-C-G
• rs1263803925
• NM_015107.3:c.2258G>C

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.2258G>C​(p.Arg753Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R753Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHF8 NM_015107.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.25
• Publications: 1 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=0.20848331).

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.2258G>C	p.Arg753Pro	missense	Exon 18 of 22	NP_055922.1	Q9UPP1-2
	PHF8	NM_001184896.1		c.2366G>C	p.Arg789Pro	missense	Exon 18 of 22	NP_001171825.1	Q9UPP1-1
	PHF8	NM_001441096.1		c.2063G>C	p.Arg688Pro	missense	Exon 17 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.2258G>C	p.Arg753Pro	missense	Exon 18 of 22	ENSP00000338868.6	Q9UPP1-2
	PHF8	ENST00000357988.9	TSL:1	c.2366G>C	p.Arg789Pro	missense	Exon 18 of 22	ENSP00000350676.5	Q9UPP1-1
	PHF8	ENST00000322659.12	TSL:1	c.2207G>C	p.Arg736Pro	missense	Exon 19 of 22	ENSP00000319473.8	Q9UPP1-5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		5.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.073
Sift	Uncertain	0.013	D
Sift4G	Benign	0.089	T
Polyphen		0.63	P
Vest4		0.41
MutPred		0.23		Loss of MoRF binding (P = 0.0052)
MVP		0.22
MPC		0.91
ClinPred		0.64	D
GERP RS		5.7
Varity_R		0.59
gMVP		0.33
Mutation Taster		=77/23	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: rs1263803925; hg19: chrX-54011532;