X-134393948-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The ENST00000370803.8(PHF6):​c.414C>T​(p.Ser138=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000522 in 1,207,879 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 5 hem., cov: 23)
Exomes 𝑓: 0.000046 ( 0 hom. 26 hem. )

Consequence

PHF6
ENST00000370803.8 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.897
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
Variant X-134393948-C-T is Benign according to our data. Variant chrX-134393948-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211900.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.
BP7
Synonymous conserved (PhyloP=0.897 with no splicing effect.
BS2
High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PHF6NM_001015877.2 linkuse as main transcriptc.414C>T p.Ser138= synonymous_variant 5/11 ENST00000370803.8 NP_001015877.1
PHF6NM_032458.3 linkuse as main transcriptc.414C>T p.Ser138= synonymous_variant 5/10 NP_115834.1
PHF6NM_032335.3 linkuse as main transcriptc.414C>T p.Ser138= synonymous_variant 5/8 NP_115711.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PHF6ENST00000370803.8 linkuse as main transcriptc.414C>T p.Ser138= synonymous_variant 5/111 NM_001015877.2 ENSP00000359839 P4Q8IWS0-1

Frequencies

GnomAD3 genomes
AF:
0.000108
AC:
12
AN:
111045
Hom.:
0
Cov.:
23
AF XY:
0.000150
AC XY:
5
AN XY:
33297
show subpopulations
Gnomad AFR
AF:
0.000164
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00112
Gnomad SAS
AF:
0.000371
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000377
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000115
AC:
21
AN:
183178
Hom.:
0
AF XY:
0.000148
AC XY:
10
AN XY:
67690
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00115
Gnomad SAS exome
AF:
0.000105
Gnomad FIN exome
AF:
0.0000625
Gnomad NFE exome
AF:
0.0000244
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000465
AC:
51
AN:
1096788
Hom.:
0
Cov.:
29
AF XY:
0.0000718
AC XY:
26
AN XY:
362230
show subpopulations
Gnomad4 AFR exome
AF:
0.0000379
Gnomad4 AMR exome
AF:
0.0000284
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000564
Gnomad4 SAS exome
AF:
0.000296
Gnomad4 FIN exome
AF:
0.0000247
Gnomad4 NFE exome
AF:
0.0000143
Gnomad4 OTH exome
AF:
0.0000434
GnomAD4 genome
AF:
0.000108
AC:
12
AN:
111091
Hom.:
0
Cov.:
23
AF XY:
0.000150
AC XY:
5
AN XY:
33353
show subpopulations
Gnomad4 AFR
AF:
0.000163
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00113
Gnomad4 SAS
AF:
0.000372
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000377
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000113

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 18, 2016- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMay 04, 2015- -
PHF6-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 26, 2022This 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). -
Borjeson-Forssman-Lehmann syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 14, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
7.3
DANN
Benign
0.70
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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.

Other links and lift over

dbSNP: rs200423380; hg19: chrX-133527978; COSMIC: COSV59700060; API