chrX-53985226-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_015107.3(PHF8):c.2131G>A(p.Glu711Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0013 in 1,189,248 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 456 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E711A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., 25 hem., cov: 22)

Exomes 𝑓: 0.0013 ( 0 hom. 431 hem. )

Consequence

PHF8
NM_015107.3 missense, splice_region

Scores

Splicing: ADA: 0.9707

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.90

Publications

5 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, Labcorp Genetics (formerly Invitae), G2P

PHF8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant X-53985226-C-T is Benign according to our data. Variant chrX-53985226-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000833 (93/111579) while in subpopulation NFE AF = 0.00156 (83/53117). AF 95% confidence interval is 0.00129. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 25 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF8	NM_015107.3 link	c.2131G>A	p.Glu711Lys	missense_variant, splice_region_variant	Exon 18 of 22	ENST00000338154.11	NP_055922.1	Q9UPP1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF8	ENST00000338154.11 link	c.2131G>A	p.Glu711Lys	missense_variant, splice_region_variant	Exon 18 of 22	1	NM_015107.3	ENSP00000338868.6		Q9UPP1-2

Frequencies

GnomAD3 genomes

AF:

0.000834

AC:

AN:

111524

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000952

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000693

AC:

106

AN:

152869

AF XY:

0.000644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000815

Gnomad ASJ exome

AF:

0.000145

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000743

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00134

AC:

1448

AN:

1077669

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

431

AN XY:

346893

show subpopulations

African (AFR)

AF:

0.0000772

AC:

AN:

25908

American (AMR)

AF:

0.0000602

AC:

AN:

33200

Ashkenazi Jewish (ASJ)

AF:

0.0000525

AC:

AN:

19034

East Asian (EAS)

AF:

0.0000339

AC:

AN:

29477

South Asian (SAS)

AF:

0.000308

AC:

AN:

51866

European-Finnish (FIN)

AF:

0.0000252

AC:

AN:

39666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4067

European-Non Finnish (NFE)

AF:

0.00169

AC:

1402

AN:

829055

Other (OTH)

AF:

0.000507

AC:

AN:

45396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

148

198

247

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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

AF:

0.000833

AC:

AN:

111579

Hom.:

Cov.:

AF XY:

0.000739

AC XY:

AN XY:

33807

show subpopulations

African (AFR)

AF:

0.000293

AC:

AN:

30737

American (AMR)

AF:

0.0000951

AC:

AN:

10519

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3531

South Asian (SAS)

AF:

0.00

AC:

AN:

2643

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00156

AC:

AN:

53117

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00123

Hom.:

Bravo

AF:

0.000835

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00138

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00178

AC:

ExAC

AF:

0.000483

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Aug 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 15, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 10, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

PHF8-related disorder

Benign:1

Mar 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.041

.;T;.;.

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.056

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.90

.;L;.;.

PhyloP100

5.9

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.099

Sift

Uncertain

0.013

D;D;D;D

Sift4G

Benign

0.064

T;T;T;D

Polyphen

0.99

D;D;.;.

Vest4

0.23

MVP

0.32

MPC

1.0

ClinPred

0.061

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.39

gMVP

0.48

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over