NM_001017368.2:c.440G>C

Variant names:

• chr17-35021522-C-G
• rs34747500
• NM_001017368.2:c.440G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001017368.2(RFFL):​c.440G>C​(p.Arg147Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RFFL NM_001017368.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.104708135).

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.440G>C	p.Arg147Pro	missense	Exon 3 of 7	NP_001017368.1	Q8WZ73-1
	RFFL	NR_037713.2		n.570G>C		non_coding_transcript_exon	Exon 3 of 7
	RAD51L3-RFFL	NR_037714.1		n.656-4942G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFFL	ENST00000394597.7	TSL:1 MANE Select	c.440G>C	p.Arg147Pro	missense	Exon 3 of 7	ENSP00000378096.3	Q8WZ73-1
	ENSG00000267618	ENST00000593039.5	TSL:2	c.427-4942G>C		intron	N/A	ENSP00000466834.1	K7EN88
	RFFL	ENST00000948502.1		c.440G>C	p.Arg147Pro	missense	Exon 3 of 8	ENSP00000618561.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458188 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725248

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25714

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110164

Other (OTH) AF: 0.00 AC: 0 AN: 60210

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.11
DANN	Benign	0.72
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.3	L
PhyloP100		-1.1
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.097
Sift	Benign	0.25	T
Sift4G	Benign	0.28	T
Polyphen		0.59	P
Vest4		0.41
MutPred		0.28		Gain of glycosylation at S149 (P = 0.0364)
MVP		0.24
MPC		0.73
ClinPred		0.65	D
GERP RS		-4.3
PromoterAI		-0.0044	Neutral
Varity_R		0.13
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

Other links and lift over

dbSNP: rs34747500; hg19: chr17-33348541;