X-134377731-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001015877.2(PHF6):c.114G>T(p.Lys38Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Extended PHD1 domain (ePHD1) (size 118) in uniprot entity PHF6_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_001015877.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF6	NM_001015877.2	c.114G>T	p.Lys38Asn	missense_variant	2/11	ENST00000370803.8
PHF6	NM_032458.3	c.114G>T	p.Lys38Asn	missense_variant	2/10
PHF6	NM_032335.3	c.114G>T	p.Lys38Asn	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF6	ENST00000370803.8	c.114G>T	p.Lys38Asn	missense_variant	2/11	1	NM_001015877.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

PHF6: PM2, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.072	T;T;T;.;.
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Uncertain	0.088	D
MutationAssessor	Benign	1.0	L;L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	1.7	N;N;.;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.89	T;T;.;T;T
Sift4G	Uncertain	0.055	T;T;T;T;D
Polyphen		0.70	P;P;.;.;D
Vest4		0.59
MutPred		0.37		Loss of methylation at K38 (P = 0.0012);Loss of methylation at K38 (P = 0.0012);Loss of methylation at K38 (P = 0.0012);Loss of methylation at K38 (P = 0.0012);Loss of methylation at K38 (P = 0.0012);
MVP		0.87
MPC		1.9
ClinPred		0.91	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.38
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-133511761;