rs761247075

Variant names:

• chr6-33415077-C-T
• rs761247075
• NM_024165.3:c.1172C>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.1172C>T​(p.Ser391Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PHF1 NM_024165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• 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=0.06289217).
• BS2: High AC in GnomAd4 at 5 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.1172C>T	p.Ser391Leu	missense	Exon 12 of 15	NP_077084.2	O43189-1
	PHF1	NM_002636.5		c.1161C>T	p.Leu387Leu	synonymous	Exon 12 of 14	NP_002627.2	O43189-2
	PHF1	NR_027692.2		n.1379C>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.1172C>T	p.Ser391Leu	missense	Exon 12 of 15	ENSP00000363640.3	O43189-1
	PHF1	ENST00000374512.7	TSL:1	c.1161C>T	p.Leu387Leu	synonymous	Exon 12 of 14	ENSP00000363636.3	O43189-2
	PHF1	ENST00000859011.1		c.1190C>T	p.Ser397Leu	missense	Exon 12 of 15	ENSP00000529070.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 244094 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1459888 Hom.: 0 Cov.: 37 AF XY: 0.0000207 AC XY: 15 AN XY: 726176

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111120

Other (OTH) AF: 0.0000498 AC: 3 AN: 60272

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74416

African (AFR) AF: 0.00 AC: 0 AN: 41506

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67970

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000474 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.00144 AC: 5 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	0.070
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.079
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.062
Sift	Benign	0.11	T
Sift4G	Benign	0.29	T
Polyphen		0.0040	B
Vest4		0.15
MutPred		0.33		Gain of sheet (P = 0.0061)
MVP		0.13
MPC		0.16
ClinPred		0.096	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.36
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs761247075; hg19: chr6-33382854;