chr5-140303060-A-G

Variant names:

• chr5-140303060-A-G
• rs1561523770
• NM_002622.5:c.14T>C

Variant summary

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

The NM_002622.5(PFDN1):​c.14T>C​(p.Val5Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PFDN1 NM_002622.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

PFDN1 (HGNC:8866): (prefoldin subunit 1) 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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFDN1	NM_002622.5	c.14T>C	p.Val5Ala	missense_variant	Exon 1 of 4	ENST00000261813.9	NP_002613.2
PFDN1	XM_005268465.5	c.14T>C	p.Val5Ala	missense_variant	Exon 1 of 4		XP_005268522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFDN1	ENST00000261813.9	c.14T>C	p.Val5Ala	missense_variant	Exon 1 of 4	1	NM_002622.5	ENSP00000261813.4
PFDN1	ENST00000524074.1	c.14T>C	p.Val5Ala	missense_variant	Exon 1 of 5	5		ENSP00000428707.1
PFDN1	ENST00000510217.1	c.14T>C	p.Val5Ala	missense_variant	Exon 1 of 3	2		ENSP00000426383.1
PFDN1	ENST00000507185.1	n.27T>C		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251456 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000205 AC: 3 AN: 1460710 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726786

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14T>C (p.V5A) alteration is located in exon 1 (coding exon 1) of the PFDN1 gene. This alteration results from a T to C substitution at nucleotide position 14, causing the valine (V) at amino acid position 5 to be replaced by an alanine (A). 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	0.62
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.2	N;D;N
REVEL	Benign	0.12
Sift	Benign	0.044	D;.;D
Sift4G	Benign	0.47	T;.;T
Polyphen		0.020	B;.;.
Vest4		0.61
MutPred		0.29		Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);Gain of disorder (P = 0.0266);
MVP		0.62
MPC		0.50
ClinPred		0.88	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.26
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs1561523770; hg19: chr5-139682645;