17-35016525-A-C

Position:

• chr17-35016525-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001017368.2(RFFL):​c.731T>G​(p.Leu244Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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: RFFL NM_001017368.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

RFFL (HGNC:24821): (ring finger and FYVE like domain containing E3 ubiquitin protein ligase) Enables enzyme binding activity; p53 binding activity; and ubiquitin protein ligase activity. Involved in cellular protein metabolic process; negative regulation of cysteine-type endopeptidase activity involved in execution phase of apoptosis; and negative regulation of signal transduction. Located in endosome membrane and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RAD51L3-RFFL (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFFL	NM_001017368.2	c.731T>G	p.Leu244Arg	missense_variant	5/7	ENST00000394597.7	NP_001017368.1
RAD51L3-RFFL	NR_037714.1	n.711T>G		non_coding_transcript_exon_variant	6/7
RFFL	NR_037713.2	n.861T>G		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFFL	ENST00000394597.7	c.731T>G	p.Leu244Arg	missense_variant	5/7	1	NM_001017368.2	ENSP00000378096	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2023

The c.731T>G (p.L244R) alteration is located in exon 5 (coding exon 4) of the RFFL gene. This alteration results from a T to G substitution at nucleotide position 731, causing the leucine (L) at amino acid position 244 to be replaced by an arginine (R). 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	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;D;D;D;.;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;.;.;D;D;D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.8	M;.;M;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.2	D;.;D;.;.;D;.;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.;D;.;.;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;.;D
Polyphen		1.0	D;D;D;D;D;D;.;.
Vest4		0.91
MutPred		0.48		Loss of stability (P = 0.0295);.;Loss of stability (P = 0.0295);Loss of stability (P = 0.0295);Loss of stability (P = 0.0295);Loss of stability (P = 0.0295);.;.;
MVP		0.77
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-33343544;