rs368222331

Variant names:

• chr6-33415085-C-T
• rs368222331
• NM_024165.3:c.1180C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_024165.3(PHF1):​c.1180C>T​(p.Arg394Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,612,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PHF1 NM_024165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.844
• Publications: 0 publications found

Genes affected

PHF1 (HGNC:8919): (PHD finger protein 1) This gene encodes a Polycomb group protein. The protein is a component of a histone H3 lysine-27 (H3K27)-specific methyltransferase complex, and functions in transcriptional repression of homeotic genes. The protein is also recruited to double-strand breaks, and reduced protein levels results in X-ray sensitivity and increased homologous recombination. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.044749975).
• BS2: High AC in GnomAd4 at 15 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024165.3. 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
	PHF1	NM_024165.3	MANE Select	c.1180C>T	p.Arg394Cys	missense	Exon 12 of 15	NP_077084.2	O43189-1
	PHF1	NM_002636.5		c.1169C>T	p.Ala390Val	missense	Exon 12 of 14	NP_002627.2	O43189-2
	PHF1	NR_027692.2		n.1387C>T		non_coding_transcript_exon	Exon 12 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF1	ENST00000374516.8	TSL:1 MANE Select	c.1180C>T	p.Arg394Cys	missense	Exon 12 of 15	ENSP00000363640.3	O43189-1
	PHF1	ENST00000374512.7	TSL:1	c.1169C>T	p.Ala390Val	missense	Exon 12 of 14	ENSP00000363636.3	O43189-2
	PHF1	ENST00000859011.1		c.1198C>T	p.Arg400Cys	missense	Exon 12 of 15	ENSP00000529070.1

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000935 AC: 23 AN: 245990 AF XY: 0.000113

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000146

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000202 AC: 295 AN: 1460558 Hom.: 0 Cov.: 38 AF XY: 0.000198 AC XY: 144 AN XY: 726520

African (AFR) AF: 0.0000299 AC: 1 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.000225 AC: 250 AN: 1111386

Other (OTH) AF: 0.000431 AC: 26 AN: 60324

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74266

African (AFR) AF: 0.0000242 AC: 1 AN: 41372

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000907 AC: 11

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.84
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.069
Sift	Benign	0.11	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.18
MVP		0.17
ClinPred		0.075	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.13
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs368222331; hg19: chr6-33382862;