rs1556018932

Positions:

• chrX-134413910-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001015877.2(PHF6):​c.673C>T​(p.Arg225Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHF6 NM_001015877.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.33

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-134413910-C-T is Pathogenic according to our data. Variant chrX-134413910-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 488410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHF6	NM_001015877.2	c.673C>T	p.Arg225Ter	stop_gained	7/11	ENST00000370803.8	NP_001015877.1
PHF6	NM_032458.3	c.673C>T	p.Arg225Ter	stop_gained	7/10		NP_115834.1
PHF6	NM_032335.3	c.676C>T	p.Arg226Ter	stop_gained	7/8		NP_115711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHF6	ENST00000370803.8	c.673C>T	p.Arg225Ter	stop_gained	7/11	1	NM_001015877.2	ENSP00000359839	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2021

The c.673C>T (p.R225*) alteration, located in exon 7 (coding exon 6) of the PHF6 gene, consists of a C to T substitution at nucleotide position 673. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 225. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was detected as heterozygous and maternally inherited in a pediatric female Chinese patient with developmental delay, short stature, dysmorphic facial features, finger and toe abnormalities, hyperpigmentation, and complete growth hormone deficiency (Zhang, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2022

De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12415272, 20228800, 26103525, 27602765, 30280491, 31475166, 36008597, 21736506, 30630810) -

Borjeson-Forssman-Lehmann syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Pediatric Research, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine

Oct 11, 2017

Intellectual disability -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.85	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.94
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1556018932; hg19: chrX-133547940; COSMIC: COSV59699600;