rs188961105

chrX-134413970-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001015877.2(PHF6):c.729+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,206,976 control chromosomes in the GnomAD database, including 12 homozygotes. There are 370 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 0.0063 (5 hom., 171 hem., cov: 22)
  • Exomes 𝑓: 0.00072 (7 hom. 199 hem.)
• Consequence: PHF6 NM_001015877.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.1190
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.93

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-134413970-A-G is Benign according to our data. Variant chrX-134413970-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129886.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=4}. Variant chrX-134413970-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00629 (698/110885) while in subpopulation AFR AF= 0.0218 (665/30526). AF 95% confidence interval is 0.0204. There are 5 homozygotes in gnomad4. There are 171 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF6	NM_001015877.2	c.729+4A>G		splice_donor_region_variant, intron_variant		ENST00000370803.8
PHF6	NM_032335.3	c.732+4A>G		splice_donor_region_variant, intron_variant
PHF6	NM_032458.3	c.729+4A>G		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF6	ENST00000370803.8	c.729+4A>G		splice_donor_region_variant, intron_variant		1	NM_001015877.2	P4

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 698 AN: 110833 Hom.: 5 Cov.: 22 AF XY: 0.00518 AC XY: 171 AN XY: 33027

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00232

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.00271

GnomAD3 exomes AF: 0.00198 AC: 363 AN: 183199 Hom.: 5 AF XY: 0.00109 AC XY: 74 AN XY: 67723

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000612

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000719 AC: 788 AN: 1096091 Hom.: 7 Cov.: 30 AF XY: 0.000550 AC XY: 199 AN XY: 361589

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.00629 AC: 698 AN: 110885 Hom.: 5 Cov.: 22 AF XY: 0.00517 AC XY: 171 AN XY: 33089

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.00232

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000755

Gnomad4 OTH AF: 0.00268

Alfa AF: 0.00365 Hom.: 15

Bravo AF: 0.00771

EpiCase AF: 0.0000547

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 14, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

PHF6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2019

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

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2016

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. -

Borjeson-Forssman-Lehmann syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	17
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.27
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

Other links and lift over

dbSNP: rs188961105; hg19: chrX-133548000;