rs199945885

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001015877.2(PHF6):c.487C>T(p.Arg163Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000472 in 1,208,663 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000045 ( 0 hom. 16 hem. )

Consequence

PHF6
NM_001015877.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:3B:2O:1

Conservation

PhyloP100: 3.73

Variant links:

Genes affected

PHF6 (HGNC:18145): (PHD finger protein 6) This gene is a member of the plant homeodomain (PHD)-like finger (PHF) family. It encodes a protein with two PHD-type zinc finger domains, indicating a potential role in transcriptional regulation, that localizes to the nucleolus. Mutations affecting the coding region of this gene or the splicing of the transcript have been associated with Borjeson-Forssman-Lehmann syndrome (BFLS), a disorder characterized by cognitive disability, epilepsy, hypogonadism, hypometabolism, obesity, swelling of subcutaneous tissue of the face, narrow palpebral fissures, and large ears. Alternate splicing results in multiple transcript variants, encoding different isoforms. [provided by RefSeq, Jun 2010]

PHF6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2284007).

BP6

Variant X-134413559-C-T is Benign according to our data. Variant chrX-134413559-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 135031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF6	NM_001015877.2 link	c.487C>T	p.Arg163Cys	missense_variant	Exon 6 of 11	ENST00000370803.8	NP_001015877.1	Q8IWS0-1
PHF6	NM_032458.3 link	c.487C>T	p.Arg163Cys	missense_variant	Exon 6 of 10		NP_115834.1	Q8IWS0-1
PHF6	NM_032335.3 link	c.490C>T	p.Arg164Cys	missense_variant	Exon 6 of 8		NP_115711.2	Q8IWS0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF6	ENST00000370803.8 link	c.487C>T	p.Arg163Cys	missense_variant	Exon 6 of 11	1	NM_001015877.2	ENSP00000359839.4		Q8IWS0-1

Frequencies

GnomAD3 genomes

AF:

0.0000720

AC:

AN:

111183

Hom.:

Cov.:

AF XY:

0.0000897

AC XY:

AN XY:

33453

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000603

AC:

AN:

182563

Hom.:

AF XY:

0.0000595

AC XY:

AN XY:

67221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000135

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1097426

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

362878

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000569

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000511

Gnomad4 OTH exome

AF:

0.0000651

GnomAD4 genome

AF:

0.0000719

AC:

AN:

111237

Hom.:

Cov.:

AF XY:

0.0000895

AC XY:

AN XY:

33517

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Borjeson-Forssman-Lehmann syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 08, 2024	- -

PHF6-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 17, 2024

The PHF6 c.487C>T variant is predicted to result in the amino acid substitution p.Arg163Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including in 4 hemizygous individuals. Although we suspect this variant may possibly be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;T;T;.;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

.;D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.23

T;T;T;T;T

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

1.7

L;L;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.4

N;N;.;N;N

REVEL

Uncertain

0.49

Sift

Uncertain

0.0040

D;D;.;D;D

Sift4G

Uncertain

0.022

D;D;D;D;D

Polyphen

1.0

D;D;.;.;D

Vest4

0.32

MVP

0.89

MPC

2.4

ClinPred

0.31

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over