Genetic Variant PHF11:p.Ala15Pro (chr13-49496044-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001040443.3(PHF11):c.43G>C(p.Ala15Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000757 in 1,320,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A15S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

PHF11
NM_001040443.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.248

Publications

0 publications found

Variant links:

Genes affected

PHF11 (HGNC:17024): (PHD finger protein 11) This gene encodes a protein containing a PHD (plant homeodomain) type zinc finger. This gene has been identified in some studies as a candidate gene for asthma. Naturally-occurring readthrough transcription may occur from the upstream SETDB2 (SET domain bifurcated 2) gene to this locus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

PHF11 links:

SETDB2-PHF11 (HGNC:):

SETDB2-PHF11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07406917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF11	NM_001040443.3 link	c.43G>C	p.Ala15Pro	missense_variant	Exon 1 of 10	ENST00000378319.8	NP_001035533.1	Q9UIL8-1B4DDL5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF11	ENST00000378319.8 link	c.43G>C	p.Ala15Pro	missense_variant	Exon 1 of 10	1	NM_001040443.3	ENSP00000367570.3		Q9UIL8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.57e-7

AC:

AN:

1320206

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

650782

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26602

American (AMR)

AF:

0.00

AC:

AN:

26080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23034

East Asian (EAS)

AF:

0.00

AC:

AN:

28256

South Asian (SAS)

AF:

0.00

AC:

AN:

73170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32696

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4944

European-Non Finnish (NFE)

AF:

9.52e-7

AC:

AN:

1050660

Other (OTH)

AF:

0.00

AC:

AN:

54764

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.43G>C (p.A15P) alteration is located in exon 1 (coding exon 1) of the PHF11 gene. This alteration results from a G to C substitution at nucleotide position 43, causing the alanine (A) at amino acid position 15 to be replaced by a proline (P). 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

0.086

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.2

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.37

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.074

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

PhyloP100

-0.25

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.81

N;.

REVEL

Benign

0.072

Sift

Uncertain

0.0060

D;.

Sift4G

Benign

0.12

T;T

Polyphen

0.0010

B;P

Vest4

0.060

MutPred

0.17

Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);

MVP

0.53

MPC

0.57

ClinPred

0.18

GERP RS

-0.34

PromoterAI

0.043

Neutral

(source)

Varity_R

0.15

gMVP

0.30

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over