Genetic Variant PHF1:p.Pro371Leu (chr6-33415017-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_024165.3(PHF1):c.1112C>T(p.Pro371Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,572,278 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

PHF1
NM_024165.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.26

Variant links:

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]

PHF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031372786).

BS2

High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF1	NM_024165.3 link	c.1112C>T	p.Pro371Leu	missense_variant	Exon 12 of 15	ENST00000374516.8	NP_077084.2	O43189-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF1	ENST00000374516.8 link	c.1112C>T	p.Pro371Leu	missense_variant	Exon 12 of 15	1	NM_024165.3	ENSP00000363640.3		O43189-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151920

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000165

AC:

AN:

181640

Hom.:

AF XY:

0.0000102

AC XY:

AN XY:

98398

show subpopulations

Gnomad AFR exome

AF:

0.0000939

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1420358

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

703412

show subpopulations

Gnomad4 AFR exome

AF:

0.0000311

Gnomad4 AMR exome

AF:

0.0000266

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000293

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151920

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1112C>T (p.P371L) alteration is located in exon 12 (coding exon 11) of the PHF1 gene. This alteration results from a C to T substitution at nucleotide position 1112, causing the proline (P) at amino acid position 371 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.056

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.78

M_CAP

Benign

0.0089

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.22

REVEL

Benign

0.034

Sift

Benign

0.72

Sift4G

Benign

0.19

Polyphen

0.0

Vest4

0.17

MutPred

0.25

Loss of glycosylation at P371 (P = 0.0072);

MVP

0.19

MPC

1.1

ClinPred

0.078

GERP RS

0.99

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.033

gMVP

0.46

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over