NM_015107.3:c.2345G>C

Variant names:

• chrX-53985012-C-G
• rs782358977
• NM_015107.3:c.2345G>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.2345G>C​(p.Arg782Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,401 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R782Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000036 (0 hom. 0 hem.)
• Consequence: PHF8 NM_015107.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P

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=0.14139986).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF8	NM_015107.3	MANE Select	c.2345G>C	p.Arg782Pro	missense	Exon 18 of 22	NP_055922.1
	PHF8	NM_001184896.1		c.2453G>C	p.Arg818Pro	missense	Exon 18 of 22	NP_001171825.1
	PHF8	NM_001441096.1		c.2150G>C	p.Arg717Pro	missense	Exon 17 of 22	NP_001428025.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF8	ENST00000338154.11	TSL:1 MANE Select	c.2345G>C	p.Arg782Pro	missense	Exon 18 of 22	ENSP00000338868.6
	PHF8	ENST00000357988.9	TSL:1	c.2453G>C	p.Arg818Pro	missense	Exon 18 of 22	ENSP00000350676.5
	PHF8	ENST00000322659.12	TSL:1	c.2294G>C	p.Arg765Pro	missense	Exon 19 of 22	ENSP00000319473.8

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097401 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362763

African (AFR) AF: 0.00 AC: 0 AN: 26383

American (AMR) AF: 0.00 AC: 0 AN: 35207

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841375

Other (OTH) AF: 0.00 AC: 0 AN: 46072

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability Siderius type Uncertain:1

Mar 29, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.038	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.13
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.048	D
Polyphen		0.96	D
Vest4		0.32
MVP		0.23
MPC		1.7
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.76
gMVP		0.66
Mutation Taster		=68/32	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: rs782358977; hg19: chrX-54011445;