11-66843570-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001032279.2(RCE1):​c.-194G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000007 in 1,428,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RCE1 NM_001032279.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36370248).

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>A	p.Val39Met	missense	Exon 1 of 8	NP_005124.1	Q9Y256
	RCE1	NM_001032279.2		c.-194G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001027450.1
	RCE1	NM_001032279.2		c.-194G>A		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>A	p.Val39Met	missense	Exon 1 of 8	ENSP00000309163.3	Q9Y256
	RCE1	ENST00000524849.5	TSL:1	n.115G>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000436300.1	E9PPV9
	RCE1	ENST00000524506.5	TSL:5	c.115G>A	p.Val39Met	missense	Exon 1 of 7	ENSP00000436600.1	E9PI08

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 194444 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 7.00e-7 AC: 1 AN: 1428028 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 709170

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 1103294

Other (OTH) AF: 0.0000168 AC: 1 AN: 59402

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000874 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.075
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.088	T
Polyphen		0.84	P
Vest4		0.47
MutPred		0.44		Gain of catalytic residue at V39 (P = 0.346)
MVP		0.24
MPC		0.95
ClinPred		0.96	D
GERP RS		3.6
PromoterAI		-0.0073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.24
gMVP		0.38
Mutation Taster		=77/23	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;