20-54214351-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002623.4(PFDN4):c.25G>C(p.Ala9Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,387,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PFDN4
NM_002623.4 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.41

Publications

0 publications found

Variant links:

Genes affected

PFDN4 (HGNC:8868): (prefoldin subunit 4) This gene encodes a member of the prefoldin beta subunit family. The encoded protein is one of six subunits of prefoldin, a molecular chaperone complex that binds and stabilizes newly synthesized polypeptides, thereby allowing them to fold correctly. The complex, consisting of two alpha and four beta subunits, forms a double beta barrel assembly with six protruding coiled-coils. [provided by RefSeq, Jul 2008]

PFDN4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFDN4	NM_002623.4 link	c.25G>C	p.Ala9Pro	missense_variant, splice_region_variant	Exon 2 of 4	ENST00000371419.7	NP_002614.2	Q9NQP4
PFDN4	XM_047440198.1 link	c.271G>C	p.Ala91Pro	missense_variant, splice_region_variant	Exon 2 of 4		XP_047296154.1
PFDN4	XM_017027879.2 link	c.166G>C	p.Ala56Pro	missense_variant, splice_region_variant	Exon 2 of 4		XP_016883368.1
PFDN4	XM_047440199.1 link	c.271G>C	p.Ala91Pro	missense_variant, splice_region_variant	Exon 2 of 3		XP_047296155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFDN4	ENST00000371419.7 link	c.25G>C	p.Ala9Pro	missense_variant, splice_region_variant	Exon 2 of 4	1	NM_002623.4	ENSP00000360473.2		Q9NQP4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1387332

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693026

show subpopulations

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

African (AFR)

AF:

0.0000322

AC:

AN:

31084

American (AMR)

AF:

0.00

AC:

AN:

38894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25190

East Asian (EAS)

AF:

0.00

AC:

AN:

39030

South Asian (SAS)

AF:

0.00

AC:

AN:

80550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53052

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4022

European-Non Finnish (NFE)

AF:

9.45e-7

AC:

AN:

1057802

Other (OTH)

AF:

0.00

AC:

AN:

57708

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.0000555

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.25G>C (p.A9P) alteration is located in exon 2 (coding exon 2) of the PFDN4 gene. This alteration results from a G to C substitution at nucleotide position 25, causing the alanine (A) at amino acid position 9 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

0.27

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.096

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.75

M_CAP

Benign

0.0076

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.88

PhyloP100

9.4

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.010

REVEL

Benign

0.18

Sift

Benign

0.14

Sift4G

Benign

0.13

Polyphen

0.0020

Vest4

0.37

MutPred

0.26

Loss of helix (P = 0.0033);

MVP

0.65

MPC

0.84

ClinPred

0.89

GERP RS

5.0

Varity_R

0.32

gMVP

0.59

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.17

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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20-54214351-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over