X-134377648-C-T

Variant names:

• chrX-134377648-C-T
• rs2077283804
• NM_001015877.2:c.31C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001015877.2(PHF6):​c.31C>T​(p.Pro11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,096,874 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 1 hem.)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.064489484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF6	NM_001015877.2	c.31C>T	p.Pro11Ser	missense_variant	Exon 2 of 11	ENST00000370803.8	NP_001015877.1
PHF6	NM_032458.3	c.31C>T	p.Pro11Ser	missense_variant	Exon 2 of 10		NP_115834.1
PHF6	NM_032335.3	c.31C>T	p.Pro11Ser	missense_variant	Exon 2 of 8		NP_115711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF6	ENST00000370803.8	c.31C>T	p.Pro11Ser	missense_variant	Exon 2 of 11	1	NM_001015877.2	ENSP00000359839.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1096874 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362318

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000832

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Borjeson-Forssman-Lehmann syndrome Uncertain:1

Apr 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.79
DEOGEN2	Benign	0.073	T;T;T;.;.
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.77	.;T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.064	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	-0.34	N;N;.;.;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.26	N;N;.;N;N
REVEL	Benign	0.18
Sift	Benign	0.61	T;T;.;T;T
Sift4G	Benign	0.94	T;T;T;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.064
MutPred		0.22		Gain of phosphorylation at P11 (P = 0.0191);Gain of phosphorylation at P11 (P = 0.0191);Gain of phosphorylation at P11 (P = 0.0191);Gain of phosphorylation at P11 (P = 0.0191);Gain of phosphorylation at P11 (P = 0.0191);
MVP		0.60
MPC		1.1
ClinPred		0.091	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.054
gMVP		0.51

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

Other links and lift over

dbSNP: rs2077283804; hg19: chrX-133511678;