chr17-35014752-C-T

Variant names:

• chr17-35014752-C-T
• rs1354808886
• NM_001017368.2:c.898G>A

Variant summary

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

The NM_001017368.2(RFFL):​c.898G>A​(p.Glu300Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,580 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (1 hom.)
• Consequence: RFFL NM_001017368.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38
• Publications: 1 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.898G>A	p.Glu300Lys	missense	Exon 6 of 7	NP_001017368.1	Q8WZ73-1
	RFFL	NR_037713.2		n.1028G>A		non_coding_transcript_exon	Exon 6 of 7
	RAD51L3-RFFL	NR_037714.1		n.866+1618G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFFL	ENST00000394597.7	TSL:1 MANE Select	c.898G>A	p.Glu300Lys	missense	Exon 6 of 7	ENSP00000378096.3	Q8WZ73-1
	ENSG00000267618	ENST00000593039.5	TSL:2	c.637+1618G>A		intron	N/A	ENSP00000466834.1	K7EN88
	RFFL	ENST00000948502.1		c.940G>A	p.Glu314Lys	missense	Exon 7 of 8	ENSP00000618561.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461424 Hom.: 1 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111634

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Benign	0.086
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.091
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.047
Sift	Benign	0.19	T
Sift4G	Benign	0.86	T
Polyphen		0.16	B
Vest4		0.37
MutPred		0.40		Gain of ubiquitination at E300 (P = 0.0045)
MVP		0.43
MPC		0.35
ClinPred		0.39	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.40
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: 11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1354808886; hg19: chr17-33341771; COSMIC: COSV52071806; COSMIC: COSV52071806;