11-66845213-G-A

Variant names:

• chr11-66845213-G-A
• rs371258472
• NM_005133.3:c.667G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005133.3(RCE1):​c.667G>A​(p.Val223Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RCE1 NM_005133.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.505

Genes affected

RCE1 (HGNC:13721): (Ras converting CAAX endopeptidase 1) This gene encodes an integral membrane protein which is classified as a member of the metalloproteinase family. This enzyme is thought to function in the maintenance and processing of CAAX-type prenylated proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06658447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCE1	NM_005133.3	c.667G>A	p.Val223Met	missense_variant	Exon 6 of 8	ENST00000309657.8	NP_005124.1
RCE1	NM_001032279.2	c.355G>A	p.Val119Met	missense_variant	Exon 6 of 8		NP_001027450.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCE1	ENST00000309657.8	c.667G>A	p.Val223Met	missense_variant	Exon 6 of 8	1	NM_005133.3	ENSP00000309163.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74518

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.097	T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.53	N;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.13	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.061	T;D;D
Polyphen		0.22	B;.;.
Vest4		0.25
MutPred		0.42		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP		0.12
MPC		0.63
ClinPred		0.19	T
GERP RS		3.4
Varity_R		0.057
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371258472; hg19: chr11-66612684;