20-54214367-A-G

Variant names:

• chr20-54214367-A-G
• rs772902032
• NM_002623.4:c.41A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002623.4(PFDN4):​c.41A>G​(p.Asn14Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000041 in 1,585,988 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (1 hom.)
• Consequence: PFDN4 NM_002623.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.78
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07208392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFDN4	NM_002623.4	c.41A>G	p.Asn14Ser	missense_variant	Exon 2 of 4	ENST00000371419.7	NP_002614.2
PFDN4	XM_047440198.1	c.287A>G	p.Asn96Ser	missense_variant	Exon 2 of 4		XP_047296154.1
PFDN4	XM_017027879.2	c.182A>G	p.Asn61Ser	missense_variant	Exon 2 of 4		XP_016883368.1
PFDN4	XM_047440199.1	c.287A>G	p.Asn96Ser	missense_variant	Exon 2 of 3		XP_047296155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFDN4	ENST00000371419.7	c.41A>G	p.Asn14Ser	missense_variant	Exon 2 of 4	1	NM_002623.4	ENSP00000360473.2

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000106 AC: 26 AN: 244988 AF XY: 0.0000981

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000242

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000829

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000398 AC: 57 AN: 1433748 Hom.: 1 Cov.: 25 AF XY: 0.0000364 AC XY: 26 AN XY: 714540

African (AFR) AF: 0.0000306 AC: 1 AN: 32700

American (AMR) AF: 0.000230 AC: 10 AN: 43386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25872

East Asian (EAS) AF: 0.000483 AC: 19 AN: 39370

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 84128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4138

European-Non Finnish (NFE) AF: 0.0000229 AC: 25 AN: 1091568

Other (OTH) AF: 0.00 AC: 0 AN: 59318

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41466

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41A>G (p.N14S) alteration is located in exon 2 (coding exon 2) of the PFDN4 gene. This alteration results from a A to G substitution at nucleotide position 41, causing the asparagine (N) at amino acid position 14 to be replaced by a serine (S). 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	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Benign	0.093	T
Sift4G	Benign	0.080	T
Polyphen		0.0020	B
Vest4		0.32
MutPred		0.26		Gain of phosphorylation at N14 (P = 0.053);
MVP		0.65
MPC		0.52
ClinPred		0.11	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.071
gMVP		0.41
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs772902032; hg19: chr20-52830906; COSMIC: COSV65063883;