X-54014554-G-T

Variant names:

• chrX-54014554-G-T
• rs77581173
• NM_015107.3:c.606C>A

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.606C>A​(p.Asn202Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,086,533 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N202N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: PHF8 NM_015107.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200
• Publications: 3 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=0.25797835).

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.606C>A	p.Asn202Lys	missense	Exon 7 of 22	NP_055922.1	Q9UPP1-2
	PHF8	NM_001184896.1		c.714C>A	p.Asn238Lys	missense	Exon 7 of 22	NP_001171825.1	Q9UPP1-1
	PHF8	NM_001441096.1		c.714C>A	p.Asn238Lys	missense	Exon 7 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.606C>A	p.Asn202Lys	missense	Exon 7 of 22	ENSP00000338868.6	Q9UPP1-2
	PHF8	ENST00000357988.9	TSL:1	c.714C>A	p.Asn238Lys	missense	Exon 7 of 22	ENSP00000350676.5	Q9UPP1-1
	PHF8	ENST00000322659.12	TSL:1	c.606C>A	p.Asn202Lys	missense	Exon 7 of 22	ENSP00000319473.8	Q9UPP1-5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1086533 Hom.: 0 Cov.: 28 AF XY: 0.00000284 AC XY: 1 AN XY: 352417

African (AFR) AF: 0.00 AC: 0 AN: 26211

American (AMR) AF: 0.00 AC: 0 AN: 35127

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19300

East Asian (EAS) AF: 0.00 AC: 0 AN: 30147

South Asian (SAS) AF: 0.00 AC: 0 AN: 53660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4037

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 831894

Other (OTH) AF: 0.00 AC: 0 AN: 45719

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.0020
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.080
Sift	Benign	0.064	T
Sift4G	Benign	0.13	T
Polyphen		0.24	B
Vest4		0.30
MutPred		0.42		Gain of solvent accessibility (P = 0.0221)
MVP		0.61
MPC		2.8
ClinPred		0.89	D
GERP RS		2.9
PromoterAI		0.0027	Neutral
Varity_R		0.64
gMVP		0.94
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77581173; hg19: chrX-54040987;