NM_015107.3:c.2345G>A

Variant names:

• chrX-53985012-C-T
• rs782358977
• NM_015107.3:c.2345G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015107.3(PHF8):​c.2345G>A​(p.Arg782Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,400 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes 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. R782P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 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, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07982701).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

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.2345G>A	p.Arg782Gln	missense	Exon 18 of 22	NP_055922.1	Q9UPP1-2
	PHF8	NM_001184896.1		c.2453G>A	p.Arg818Gln	missense	Exon 18 of 22	NP_001171825.1	Q9UPP1-1
	PHF8	NM_001441096.1		c.2150G>A	p.Arg717Gln	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.2345G>A	p.Arg782Gln	missense	Exon 18 of 22	ENSP00000338868.6	Q9UPP1-2
	PHF8	ENST00000357988.9	TSL:1	c.2453G>A	p.Arg818Gln	missense	Exon 18 of 22	ENSP00000350676.5	Q9UPP1-1
	PHF8	ENST00000322659.12	TSL:1	c.2294G>A	p.Arg765Gln	missense	Exon 19 of 22	ENSP00000319473.8	Q9UPP1-5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183053 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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097400 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 362762

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: 0.0000185 AC: 1 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: 0.00000119 AC: 1 AN: 841374

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

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Benign	-0.62
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.5
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.027
Sift	Benign	0.076	T
Sift4G	Benign	0.23	T
Polyphen		0.086	B
Vest4		0.092
MutPred		0.24		Loss of MoRF binding (P = 0.0451)
MVP		0.37
MPC		0.66
ClinPred		0.76	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.52
Mutation Taster		=91/9	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; COSMIC: COSV100154536; COSMIC: COSV100154536;