5-140281508-T-C

Variant names:

• chr5-140281508-T-C
• rs1302660731
• NM_002622.5:c.226A>G

Variant summary

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

The NM_002622.5(PFDN1):​c.226A>G​(p.Ile76Val) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFDN1 NM_002622.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83

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]

CYSTM1 (HGNC:30239): (cysteine rich transmembrane module containing 1) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

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=0.23650208).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFDN1	NM_002622.5	c.226A>G	p.Ile76Val	missense_variant	Exon 3 of 4	ENST00000261813.9	NP_002613.2
PFDN1	XM_005268465.5	c.226A>G	p.Ile76Val	missense_variant	Exon 3 of 4		XP_005268522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFDN1	ENST00000261813.9	c.226A>G	p.Ile76Val	missense_variant	Exon 3 of 4	1	NM_002622.5	ENSP00000261813.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.226A>G (p.I76V) alteration is located in exon 3 (coding exon 3) of the PFDN1 gene. This alteration results from a A to G substitution at nucleotide position 226, causing the isoleucine (I) at amino acid position 76 to be replaced by a valine (V). 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	0.075
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.12
Sift	Benign	0.40	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.64	P;.
Vest4		0.32
MutPred		0.46		Loss of catalytic residue at L81 (P = 0.027);Loss of catalytic residue at L81 (P = 0.027);
MVP		0.39
MPC		0.41
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.15
gMVP		0.26

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: rs1302660731; hg19: chr5-139661093;