20-54219115-G-C

Position:

• chr20-54219115-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002623.4(PFDN4):​c.370G>C​(p.Gly124Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PFDN4 NM_002623.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFDN4	NM_002623.4	c.370G>C	p.Gly124Arg	missense_variant	4/4	ENST00000371419.7	NP_002614.2
PFDN4	XM_047440198.1	c.616G>C	p.Gly206Arg	missense_variant	4/4		XP_047296154.1
PFDN4	XM_017027879.2	c.511G>C	p.Gly171Arg	missense_variant	4/4		XP_016883368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFDN4	ENST00000371419.7	c.370G>C	p.Gly124Arg	missense_variant	4/4	1	NM_002623.4	ENSP00000360473.2
PFDN4	ENST00000441080.2	n.370G>C		non_coding_transcript_exon_variant	4/6	5		ENSP00000432441.1
PFDN4	ENST00000487129.1	n.674G>C		non_coding_transcript_exon_variant	5/5	2
PFDN4	ENST00000493356.5	n.489G>C		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

The c.370G>C (p.G124R) alteration is located in exon 4 (coding exon 4) of the PFDN4 gene. This alteration results from a G to C substitution at nucleotide position 370, causing the glycine (G) at amino acid position 124 to be replaced by an arginine (R). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.84		Gain of MoRF binding (P = 0.0265);
MVP		0.81
MPC		1.8
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-52835654;