X-134377694-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001015877.2(PHF6):c.77A>T(p.Lys26Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 5.80

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 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.28954965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF6	NM_001015877.2	c.77A>T	p.Lys26Met	missense_variant	2/11	ENST00000370803.8
PHF6	NM_032458.3	c.77A>T	p.Lys26Met	missense_variant	2/10
PHF6	NM_032335.3	c.77A>T	p.Lys26Met	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF6	ENST00000370803.8	c.77A>T	p.Lys26Met	missense_variant	2/11	1	NM_001015877.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

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

GeneDx

Jun 20, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.092	T;T;T;.;.
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Benign	0.97	L;L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.050	N;N;.;N;N
REVEL	Benign	0.29
Sift	Benign	0.23	T;T;.;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.011	B;B;.;.;B
Vest4		0.39
MutPred		0.31		Gain of catalytic residue at K26 (P = 0.0012);Gain of catalytic residue at K26 (P = 0.0012);Gain of catalytic residue at K26 (P = 0.0012);Gain of catalytic residue at K26 (P = 0.0012);Gain of catalytic residue at K26 (P = 0.0012);
MVP		0.81
MPC		1.5
ClinPred		0.69	D
GERP RS		5.8
Varity_R		0.40
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs2077284287; hg19: chrX-133511724;