20-54215339-A-C

Position:

• chr20-54215339-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002623.4(PFDN4):​c.172A>C​(p.Met58Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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)
• Consequence: PFDN4 NM_002623.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15102854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PFDN4	NM_002623.4	c.172A>C	p.Met58Leu	missense_variant	3/4	ENST00000371419.7	NP_002614.2
PFDN4	XM_047440198.1	c.418A>C	p.Met140Leu	missense_variant	3/4		XP_047296154.1
PFDN4	XM_017027879.2	c.313A>C	p.Met105Leu	missense_variant	3/4		XP_016883368.1
PFDN4	XM_047440199.1	c.*8A>C		3_prime_UTR_variant	3/3		XP_047296155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PFDN4	ENST00000371419.7	c.172A>C	p.Met58Leu	missense_variant	3/4	1	NM_002623.4	ENSP00000360473.2
PFDN4	ENST00000441080.2	n.172A>C		non_coding_transcript_exon_variant	3/6	5		ENSP00000432441.1
PFDN4	ENST00000487129.1	n.476A>C		non_coding_transcript_exon_variant	4/5	2
PFDN4	ENST00000493356.5	n.291A>C		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

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

May 18, 2023

The c.172A>C (p.M58L) alteration is located in exon 3 (coding exon 3) of the PFDN4 gene. This alteration results from a A to C substitution at nucleotide position 172, causing the methionine (M) at amino acid position 58 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	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.096
Sift	Benign	0.45	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.33
MutPred		0.56		Loss of catalytic residue at M58 (P = 0.0099);
MVP		0.32
MPC		0.60
ClinPred		0.55	D
GERP RS		2.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.17
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr20-52831878;