Genetic Variant NM_005133.3:c.596C>T (chr11-66845013-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005133.3(RCE1):c.596C>T(p.Thr199Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000208 in 1,444,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RCE1
NM_005133.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.75

Publications

1 publications found

Variant links:

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]

RCE1 links:

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ACMG classification

Classification was made for transcript

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=0.38226312).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005133.3. 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.596C>T	p.Thr199Ile	missense	Exon 5 of 8	NP_005124.1	Q9Y256
	RCE1	NM_001032279.2		c.284C>T	p.Thr95Ile	missense	Exon 5 of 8	NP_001027450.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RCE1	ENST00000309657.8	TSL:1 MANE Select	c.596C>T	p.Thr199Ile	missense	Exon 5 of 8	ENSP00000309163.3	Q9Y256
RCE1	ENST00000524849.5	TSL:1	n.*283C>T		non_coding_transcript_exon	Exon 5 of 8	ENSP00000436300.1	E9PPV9
RCE1	ENST00000524849.5	TSL:1	n.*283C>T		3_prime_UTR	Exon 5 of 8	ENSP00000436300.1	E9PPV9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000419

AC:

AN:

238518

AF XY:

0.00000779

show subpopulations

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:

0.000172

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1444276

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

716170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33170

American (AMR)

AF:

0.00

AC:

AN:

43716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25070

East Asian (EAS)

AF:

0.00

AC:

AN:

39452

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52734

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1100966

Other (OTH)

AF:

0.0000168

AC:

AN:

59580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.25

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.052

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.038

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0020

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.24

PhyloP100

6.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

1.2

REVEL

Benign

0.28

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.24

Vest4

0.85

MVP

0.45

MPC

0.62

ClinPred

0.35

GERP RS

4.4

Varity_R

0.24

gMVP

0.52

Mutation Taster

=38/62

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over