X-53940446-C-T

Variant names:

• chrX-53940446-C-T
• rs142630105
• NM_015107.3:c.2720G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015107.3(PHF8):​c.2720G>A​(p.Arg907His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,206,215 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,225 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., 58 hem., cov: 22)
  • Exomes 𝑓: 0.0034 (9 hom. 1167 hem.)
• Consequence: PHF8 NM_015107.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: 0.310
• Publications: 7 publications found

Genes affected

PHF8 (HGNC:20672): (PHD finger protein 8) The protein encoded by this gene is a histone lysine demethylase that preferentially acts on histones in the monomethyl or dimethyl states. The encoded protein requires Fe(2+) ion, 2-oxoglutarate, and oxygen for its catalytic activity. The protein has an N-terminal PHD finger and a central Jumonji C domain. This gene is thought to function as a transcription activator. Defects in this gene are a cause of syndromic X-linked Siderius type intellectual disability (MRXSSD) and over-expression of this gene is associated with several forms of cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

PHF8 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability Siderius type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005836606).
• BP6: Variant X-53940446-C-T is Benign according to our data. Variant chrX-53940446-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00227 (253/111382) while in subpopulation NFE AF = 0.00392 (208/53024). AF 95% confidence interval is 0.00349. There are 1 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 58 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015107.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF8	NM_015107.3	MANE Select	c.2720G>A	p.Arg907His	missense	Exon 21 of 22	NP_055922.1	Q9UPP1-2
	PHF8	NM_001184896.1		c.2828G>A	p.Arg943His	missense	Exon 21 of 22	NP_001171825.1	Q9UPP1-1
	PHF8	NM_001441096.1		c.2525G>A	p.Arg842His	missense	Exon 20 of 22	NP_001428025.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF8	ENST00000338154.11	TSL:1 MANE Select	c.2720G>A	p.Arg907His	missense	Exon 21 of 22	ENSP00000338868.6	Q9UPP1-2
	PHF8	ENST00000357988.9	TSL:1	c.2828G>A	p.Arg943His	missense	Exon 21 of 22	ENSP00000350676.5	Q9UPP1-1
	PHF8	ENST00000396282.7	TSL:5	c.2720G>A	p.Arg907His	missense	Exon 20 of 22	ENSP00000379578.3	H0Y3N9

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 254 AN: 111328 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.00227

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000835

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00267

GnomAD2 exomes AF: 0.00216 AC: 390 AN: 180726 AF XY: 0.00233

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00296

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000254

Gnomad NFE exome AF: 0.00384

Gnomad OTH exome AF: 0.00291

GnomAD4 exome AF: 0.00344 AC: 3766 AN: 1094833 Hom.: 9 Cov.: 30 AF XY: 0.00324 AC XY: 1167 AN XY: 360293

African (AFR) AF: 0.000152 AC: 4 AN: 26334

American (AMR) AF: 0.00128 AC: 45 AN: 35134

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 49 AN: 19348

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30179

South Asian (SAS) AF: 0.000334 AC: 18 AN: 53879

European-Finnish (FIN) AF: 0.000445 AC: 18 AN: 40489

Middle Eastern (MID) AF: 0.000486 AC: 2 AN: 4117

European-Non Finnish (NFE) AF: 0.00420 AC: 3525 AN: 839371

Other (OTH) AF: 0.00226 AC: 104 AN: 45982

GnomAD4 genome AF: 0.00227 AC: 253 AN: 111382 Hom.: 1 Cov.: 22 AF XY: 0.00173 AC XY: 58 AN XY: 33596

African (AFR) AF: 0.000489 AC: 15 AN: 30706

American (AMR) AF: 0.00144 AC: 15 AN: 10443

Ashkenazi Jewish (ASJ) AF: 0.00227 AC: 6 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.00 AC: 0 AN: 2629

European-Finnish (FIN) AF: 0.000835 AC: 5 AN: 5985

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00392 AC: 208 AN: 53024

Other (OTH) AF: 0.00263 AC: 4 AN: 1520

Alfa AF: 0.00367 Hom.: 172

Bravo AF: 0.00253

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00381 AC: 11

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00372 AC: 25

ExAC AF: 0.00217 AC: 263

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	1	1	Intellectual disability (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Syndromic X-linked intellectual disability Siderius type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.31
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.040
Sift	Benign	0.12	T
Sift4G	Benign	0.13	T
Polyphen		0.80	P
Vest4		0.056
MVP		0.63
MPC		1.8
ClinPred		0.019	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.16
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs142630105; hg19: chrX-53966879; COSMIC: COSV105232702; COSMIC: COSV105232702;