Genetic Variant NM_015107.3:c.606C>A (chrX-54014554-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00200

Publications

3 publications found

Variant links:

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)

PHF8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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

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.:

GnomAD4 exome

AF:

9.20e-7

AC:

AN:

1086533

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

352417

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26211

American (AMR)

AF:

0.00

AC:

AN:

35127

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19300

East Asian (EAS)

AF:

0.00

AC:

AN:

30147

South Asian (SAS)

AF:

0.00

AC:

AN:

53660

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4037

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

831894

Other (OTH)

AF:

0.00

AC:

AN:

45719

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.80

M_CAP

Benign

0.032

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

-0.0020

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.3

REVEL

Benign

0.080

Sift

Benign

0.064

Sift4G

Benign

0.13

Polyphen

0.24

Vest4

0.30

MutPred

0.42

Gain of solvent accessibility (P = 0.0221)

MVP

0.61

MPC

2.8

ClinPred

0.89

GERP RS

2.9

PromoterAI

0.0027

Neutral

(source)

Varity_R

0.64

gMVP

0.94

Mutation Taster

=53/47

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over