X-134377637-A-G

Variant names:

• chrX-134377637-A-G
• NM_001015877.2:c.20A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001015877.2(PHF6):​c.20A>G​(p.Gln7Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,097,052 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: PHF6 NM_001015877.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.90

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF6	NM_001015877.2	c.20A>G	p.Gln7Arg	missense_variant	Exon 2 of 11	ENST00000370803.8	NP_001015877.1
PHF6	NM_032458.3	c.20A>G	p.Gln7Arg	missense_variant	Exon 2 of 10		NP_115834.1
PHF6	NM_032335.3	c.20A>G	p.Gln7Arg	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.20A>G	p.Gln7Arg	missense_variant	Exon 2 of 11	1	NM_001015877.2	ENSP00000359839.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1097052 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362510

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Borjeson-Forssman-Lehmann syndrome Uncertain:1

Feb 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 7 of the PHF6 protein (p.Gln7Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PHF6-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;T;.;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	.;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.63	N;N;.;.;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N;N;.;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.010	D;D;.;D;D
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.97	D;D;.;.;D
Vest4		0.72
MutPred		0.22		Gain of MoRF binding (P = 0.0086);Gain of MoRF binding (P = 0.0086);Gain of MoRF binding (P = 0.0086);Gain of MoRF binding (P = 0.0086);Gain of MoRF binding (P = 0.0086);
MVP		1.0
MPC		1.2
ClinPred		0.67	D
GERP RS		5.8
Varity_R		0.57
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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-133511667;