22-32360291-T-C

Variant names:

• chr22-32360291-T-C
• rs750550231
• NM_001098535.1:c.413T>C

Variant summary

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

The NM_001098535.1(RFPL3):​c.413T>C​(p.Leu138Pro) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFPL3 NM_001098535.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

Genes affected

RFPL3 (HGNC:9980): (ret finger protein like 3) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in positive regulation of transcription, DNA-templated. Predicted to be located in cytoplasm. Predicted to be active in chromatin and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RFPL3S (HGNC:9981): (RFPL3 antisense)

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, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFPL3	NM_001098535.1	c.413T>C	p.Leu138Pro	missense_variant	Exon 2 of 2	ENST00000249007.4	NP_001092005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFPL3	ENST00000249007.4	c.413T>C	p.Leu138Pro	missense_variant	Exon 2 of 2	1	NM_001098535.1	ENSP00000249007.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413T>C (p.L138P) alteration is located in exon 2 (coding exon 2) of the RFPL3 gene. This alteration results from a T to C substitution at nucleotide position 413, causing the leucine (L) at amino acid position 138 to be replaced by a proline (P). 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	0.57
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	4.7	.;H
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.052	T;D
Polyphen		1.0	.;D
Vest4		0.49
MutPred		0.87		.;Loss of stability (P = 0.0127);
MVP		0.71
MPC		0.48
ClinPred		0.96	D
GERP RS		0.66
Varity_R		0.96
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs750550231; hg19: chr22-32756278;