Genetic Variant PFDN4:p.Gln95Lys (chr20-54219028-C-A) – 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_002623.4(PFDN4):c.283C>A(p.Gln95Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000509 in 1,376,048 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: not found (cov: 33)

Exomes 𝑓: 0.0000051 ( 0 hom. )

Consequence

PFDN4
NM_002623.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.06

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:

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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=0.108463824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFDN4	NM_002623.4 link	c.283C>A	p.Gln95Lys	missense_variant	Exon 4 of 4	ENST00000371419.7	NP_002614.2	Q9NQP4
PFDN4	XM_047440198.1 link	c.529C>A	p.Gln177Lys	missense_variant	Exon 4 of 4		XP_047296154.1
PFDN4	XM_017027879.2 link	c.424C>A	p.Gln142Lys	missense_variant	Exon 4 of 4		XP_016883368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFDN4	ENST00000371419.7 link	c.283C>A	p.Gln95Lys	missense_variant	Exon 4 of 4	1	NM_002623.4	ENSP00000360473.2		Q9NQP4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000173

AC:

AN:

172926

AF XY:

0.0000322

show subpopulations

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000509

AC:

AN:

1376048

Hom.:

Cov.:

AF XY:

0.00000879

AC XY:

AN XY:

682336

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30028

American (AMR)

AF:

0.00

AC:

AN:

32726

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24736

East Asian (EAS)

AF:

0.00

AC:

AN:

36662

South Asian (SAS)

AF:

0.0000536

AC:

AN:

74596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1064382

Other (OTH)

AF:

0.0000527

AC:

AN:

56972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.283C>A (p.Q95K) alteration is located in exon 4 (coding exon 4) of the PFDN4 gene. This alteration results from a C to A substitution at nucleotide position 283, causing the glutamine (Q) at amino acid position 95 to be replaced by a lysine (K). 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

0.081

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.075

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

M_CAP

Benign

0.0083

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.89

PhyloP100

3.1

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.35

REVEL

Benign

0.087

Sift

Benign

0.64

Sift4G

Benign

0.79

Polyphen

0.0020

Vest4

0.17

MutPred

0.58

Gain of ubiquitination at Q95 (P = 0.0203);

MVP

0.33

MPC

0.85

ClinPred

0.19

GERP RS

5.6

Varity_R

0.41

gMVP

0.34

Mutation Taster

=83/17

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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20-54219028-C-A

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