11-66843570-G-C

Variant names:

• chr11-66843570-G-C
• rs773546784
• NM_005133.3:c.115G>C

Variant summary

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

The NM_001032279.2(RCE1):​c.-194G>C variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000182 in 1,428,028 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: 0.000018 (0 hom.)
• Consequence: RCE1 NM_001032279.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90
• Publications: 1 publications found

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]

TOP6BL Gene-Disease associations (from GenCC):

• hydatidiform mole, recurrent, 4

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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=0.19170728).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001032279.2. 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
	RCE1	NM_005133.3	MANE Select	c.115G>C	p.Val39Leu	missense	Exon 1 of 8	NP_005124.1	Q9Y256
	RCE1	NM_001032279.2		c.-194G>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001027450.1
	RCE1	NM_001032279.2		c.-194G>C		5_prime_UTR	Exon 1 of 8	NP_001027450.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RCE1	ENST00000309657.8	TSL:1 MANE Select	c.115G>C	p.Val39Leu	missense	Exon 1 of 8	ENSP00000309163.3	Q9Y256
	RCE1	ENST00000524849.5	TSL:1	n.115G>C		non_coding_transcript_exon	Exon 1 of 8	ENSP00000436300.1	E9PPV9
	RCE1	ENST00000524506.5	TSL:5	c.115G>C	p.Val39Leu	missense	Exon 1 of 7	ENSP00000436600.1	E9PI08

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000514 AC: 1 AN: 194444 AF XY: 0.00000923

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 26 AN: 1428028 Hom.: 0 Cov.: 33 AF XY: 0.0000197 AC XY: 14 AN XY: 709170

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.0000238 AC: 1 AN: 41990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.00 AC: 0 AN: 39028

South Asian (SAS) AF: 0.00 AC: 0 AN: 83704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5328

European-Non Finnish (NFE) AF: 0.0000199 AC: 22 AN: 1103294

Other (OTH) AF: 0.0000505 AC: 3 AN: 59402

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.15
Sift	Benign	0.19	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.45		Loss of catalytic residue at V39 (P = 0.0688)
MVP		0.20
MPC		0.48
ClinPred		0.36	T
GERP RS		3.6
PromoterAI		0.00070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.21
gMVP		0.38
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs773546784; hg19: chr11-66611041;