NM_001017368.2:c.838G>C

Variant names:

• chr17-35016418-C-G
• NM_001017368.2:c.838G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001017368.2(RFFL):​c.838G>C​(p.Glu280Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 7.91
• Publications: 0 publications found

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]

ENSG00000267618 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017368.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFFL	NM_001017368.2	MANE Select	c.838G>C	p.Glu280Gln	missense	Exon 5 of 7	NP_001017368.1	Q8WZ73-1
	RFFL	NR_037713.2		n.968G>C		non_coding_transcript_exon	Exon 5 of 7
	RAD51L3-RFFL	NR_037714.1		n.818G>C		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFFL	ENST00000394597.7	TSL:1 MANE Select	c.838G>C	p.Glu280Gln	missense	Exon 5 of 7	ENSP00000378096.3	Q8WZ73-1
	ENSG00000267618	ENST00000593039.5	TSL:2	c.589G>C	p.Glu197Gln	missense	Exon 6 of 7	ENSP00000466834.1	K7EN88
	RFFL	ENST00000948502.1		c.838G>C	p.Glu280Gln	missense	Exon 5 of 8	ENSP00000618561.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.35		Gain of MoRF binding (P = 0.019)
MVP		0.58
MPC		1.0
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.55

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

Other links and lift over

hg19: chr17-33343437;