22-32358429-A-T

Variant names:

• chr22-32358429-A-T
• rs1441603287
• NM_001098535.1:c.358A>T

Variant summary

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

The NM_001098535.1(RFPL3):​c.358A>T​(p.Met120Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RFPL3 NM_001098535.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.13

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]

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=0.07371932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFPL3	NM_001098535.1	c.358A>T	p.Met120Leu	missense_variant	Exon 1 of 2	ENST00000249007.4	NP_001092005.1
RFPL3	NM_006604.2	c.271A>T	p.Met91Leu	missense_variant	Exon 2 of 3		NP_006595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFPL3	ENST00000249007.4	c.358A>T	p.Met120Leu	missense_variant	Exon 1 of 2	1	NM_001098535.1	ENSP00000249007.4
RFPL3	ENST00000397468.5	c.271A>T	p.Met91Leu	missense_variant	Exon 2 of 3	1		ENSP00000380609.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461286 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726908

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000166

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

Jun 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.358A>T (p.M120L) alteration is located in exon 1 (coding exon 1) of the RFPL3 gene. This alteration results from a A to T substitution at nucleotide position 358, causing the methionine (M) at amino acid position 120 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	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.42
DANN	Benign	0.82
DEOGEN2	Benign	0.00075	.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.033
Sift	Benign	0.32	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.22	.;B
Vest4		0.20
MutPred		0.35		.;Loss of methylation at K122 (P = 0.0613);
MVP		0.17
MPC		0.24
ClinPred		0.18	T
GERP RS		0.66
Varity_R		0.13
gMVP		0.22

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: rs1441603287; hg19: chr22-32754416;