X-54014554-G-T

Position:

• chrX-54014554-G-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.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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PHF8. . Gene score misZ 3.9759 (greater than the threshold 3.09). GenCC has associacion of gene with syndromic X-linked intellectual disability Siderius type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25797835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHF8	NM_015107.3	c.606C>A	p.Asn202Lys	missense_variant	7/22	ENST00000338154.11	NP_055922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHF8	ENST00000338154.11	c.606C>A	p.Asn202Lys	missense_variant	7/22	1	NM_015107.3	ENSP00000338868.6

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000120

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	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;T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.064	T;T;T;T
Sift4G	Benign	0.13	T;T;T;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
Varity_R		0.64
gMVP		0.94

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

Publications

LitVar

Other links and lift over

dbSNP: rs77581173; hg19: chrX-54040987;