rs762048465

Variant names:

• chrX-134373475-C-T
• rs762048465
• NM_001015877.2:c.-47+8C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001015877.2(PHF6):​c.-47+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 112,544 control chromosomes in the GnomAD database, including 1 homozygotes. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., 14 hem., cov: 23)
  • Exomes 𝑓: 0.018 (0 hom. 0 hem.)
• Consequence: PHF6 NM_001015877.2 splice_region, intron
• Scores: Splicing: ADA: 0.002068
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Borjeson-Forssman-Lehmann syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Illumina, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-134373475-C-T is Benign according to our data. Variant chrX-134373475-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 383694.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 14 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001015877.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF6	NM_001015877.2	MANE Select	c.-47+8C>T		splice_region intron	N/A	NP_001015877.1	Q8IWS0-1
	PHF6	NM_032458.3		c.-47+8C>T		splice_region intron	N/A	NP_115834.1	Q8IWS0-1
	PHF6	NM_032335.3		c.-47+8C>T		splice_region intron	N/A	NP_115711.2	Q8IWS0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF6	ENST00000370803.8	TSL:1 MANE Select	c.-47+8C>T		splice_region intron	N/A	ENSP00000359839.4	Q8IWS0-1
	PHF6	ENST00000332070.7	TSL:1	c.-47+8C>T		splice_region intron	N/A	ENSP00000329097.3	Q8IWS0-1
	PHF6	ENST00000370799.5	TSL:1	c.-47+8C>T		splice_region intron	N/A	ENSP00000359835.1	Q5JRC6

Frequencies

GnomAD3 genomes AF: 0.000489 AC: 55 AN: 112433 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.00178

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0175 AC: 1 AN: 57 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 25

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 1

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0182 AC: 1 AN: 55

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000489 AC: 55 AN: 112487 Hom.: 1 Cov.: 23 AF XY: 0.000404 AC XY: 14 AN XY: 34659

African (AFR) AF: 0.00177 AC: 55 AN: 31027

American (AMR) AF: 0.00 AC: 0 AN: 10771

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3513

South Asian (SAS) AF: 0.00 AC: 0 AN: 2685

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6255

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53169

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000604

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		1.2
PromoterAI		-0.071	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.020
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

Other links and lift over

dbSNP: rs762048465; hg19: chrX-133507505;