11-66843471-G-A

Variant names:

• chr11-66843471-G-A
• NM_005133.3:c.16G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005133.3(RCE1):​c.16G>A​(p.Gly6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000784 in 1,275,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: RCE1 NM_005133.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.30

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]

TOP6BL (HGNC:26197): (TOP6B like initiator of meiotic double strand breaks) Predicted to be involved in meiotic DNA double-strand break formation and reciprocal meiotic recombination. Predicted to be located in chromosome. Implicated in gestational trophoblastic neoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1976645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCE1	NM_005133.3	c.16G>A	p.Gly6Arg	missense_variant	Exon 1 of 8	ENST00000309657.8	NP_005124.1
TOP6BL	NM_001302084.2	c.*237G>A		3_prime_UTR_variant	Exon 15 of 15	ENST00000540737.7	NP_001289013.1
RCE1	NM_001032279.2	c.-293G>A		5_prime_UTR_variant	Exon 1 of 8		NP_001027450.1
TOP6BL	NM_024650.4	c.*237G>A		3_prime_UTR_variant	Exon 17 of 17		NP_078926.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCE1	ENST00000309657.8	c.16G>A	p.Gly6Arg	missense_variant	Exon 1 of 8	1	NM_005133.3	ENSP00000309163.3
C11orf80	ENST00000540737.7	c.*237G>A		3_prime_UTR_variant	Exon 15 of 15	2	NM_001302084.2	ENSP00000444319.1
C11orf80	ENST00000525449.6	c.*237G>A		downstream_gene_variant		1		ENSP00000434648.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.84e-7 AC: 1 AN: 1275274 Hom.: 0 Cov.: 32 AF XY: 0.00000159 AC XY: 1 AN XY: 627252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.65e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>A (p.G6R) alteration is located in exon 1 (coding exon 1) of the RCE1 gene. This alteration results from a G to A substitution at nucleotide position 16, causing the glycine (G) at amino acid position 6 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	Benign	0.25
BayesDel_addAF	Benign	0.00017	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.070
Sift	Uncertain	0.012	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.91	P;.
Vest4		0.19
MutPred		0.26		Gain of MoRF binding (P = 1e-04);Gain of MoRF binding (P = 1e-04);
MVP		0.043
MPC		0.85
ClinPred		0.96	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.28
gMVP		0.47

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: chr11-66610942;