chrX-53940321-G-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_015107.3(PHF8):c.2845C>T(p.Leu949Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,207,728 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 22)
Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )
Consequence
PHF8
NM_015107.3 missense
NM_015107.3 missense
Scores
4
3
8
Clinical Significance
Conservation
PhyloP100: 8.64
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
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=0.2825595).
BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PHF8 | NM_015107.3 | c.2845C>T | p.Leu949Phe | missense_variant | 21/22 | ENST00000338154.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PHF8 | ENST00000338154.11 | c.2845C>T | p.Leu949Phe | missense_variant | 21/22 | 1 | NM_015107.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000179 AC: 2AN: 111618Hom.: 0 Cov.: 22 AF XY: 0.0000296 AC XY: 1AN XY: 33792
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GnomAD4 exome AF: 0.00000365 AC: 4AN: 1096110Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 2AN XY: 361610
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GnomAD4 genome AF: 0.0000179 AC: 2AN: 111618Hom.: 0 Cov.: 22 AF XY: 0.0000296 AC XY: 1AN XY: 33792
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2016 | The p.L949F variant (also known as c.2845C>T), located in coding exon 20 of the PHF8 gene, results from a C to T substitution at nucleotide position 2845. The leucine at codon 949 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Syndromic X-linked intellectual disability Siderius type Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Jul 30, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;T
Polyphen
0.98
.;D;.
Vest4
MutPred
0.18
.;Loss of glycosylation at S984 (P = 0.1072);.;
MVP
MPC
2.8
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at