chrX-134393948-C-T

Variant names:

• chrX-134393948-C-T
• rs200423380
• NM_001015877.2:c.414C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001015877.2(PHF6):​c.414C>T​(p.Ser138Ser) 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 NM_001015877.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.897
• Publications: 3 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 -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 VariationId is 211900.
• BP7: Synonymous conserved (PhyloP=0.897 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 5 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.414C>T	p.Ser138Ser	synonymous	Exon 5 of 11	NP_001015877.1	Q8IWS0-1
	PHF6	NM_032458.3		c.414C>T	p.Ser138Ser	synonymous	Exon 5 of 10	NP_115834.1	Q8IWS0-1
	PHF6	NM_032335.3		c.414C>T	p.Ser138Ser	synonymous	Exon 5 of 8	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.414C>T	p.Ser138Ser	synonymous	Exon 5 of 11	ENSP00000359839.4	Q8IWS0-1
	PHF6	ENST00000332070.7	TSL:1	c.414C>T	p.Ser138Ser	synonymous	Exon 5 of 10	ENSP00000329097.3	Q8IWS0-1
	PHF6	ENST00000370799.5	TSL:1	c.414C>T	p.Ser138Ser	synonymous	Exon 5 of 9	ENSP00000359835.1	Q5JRC6

Frequencies

GnomAD3 genomes AF: 0.000108 AC: 12 AN: 111045 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.000115 AC: 21 AN: 183178 AF XY: 0.000148

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 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

African (AFR) AF: 0.0000379 AC: 1 AN: 26381

American (AMR) AF: 0.0000284 AC: 1 AN: 35195

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.000564 AC: 17 AN: 30164

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54062

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40508

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4130

European-Non Finnish (NFE) AF: 0.0000143 AC: 12 AN: 840940

Other (OTH) AF: 0.0000434 AC: 2 AN: 46041

GnomAD4 genome AF: 0.000108 AC: 12 AN: 111091 Hom.: 0 Cov.: 23 AF XY: 0.000150 AC XY: 5 AN XY: 33353

African (AFR) AF: 0.000163 AC: 5 AN: 30615

American (AMR) AF: 0.00 AC: 0 AN: 10380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00113 AC: 4 AN: 3551

South Asian (SAS) AF: 0.000372 AC: 1 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5758

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53064

Other (OTH) AF: 0.00 AC: 0 AN: 1499

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Borjeson-Forssman-Lehmann syndrome (1)
-	1	-	not provided (1)
-	-	1	not specified (1)
-	-	1	PHF6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	7.3
DANN	Benign	0.70
PhyloP100		0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

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