Genetic Variant RASL12:p.Met138Ile (chr15-65058438-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016563.4(RASL12):c.414G>A(p.Met138Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,412,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

RASL12
NM_016563.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.11

Publications

0 publications found

Variant links:

Genes affected

RASL12 (HGNC:30289): (RAS like family 12) Predicted to enable GDP binding activity; GTP binding activity; and GTPase activity. Predicted to be involved in signal transduction. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

RASL12 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016563.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASL12	NM_016563.4	MANE Select	c.414G>A	p.Met138Ile	missense	Exon 4 of 5	NP_057647.1	Q9NYN1-1
RASL12	NM_001379429.1		c.381G>A	p.Met127Ile	missense	Exon 4 of 5	NP_001366358.1	Q9NYN1-2
RASL12	NM_001307930.2		c.357G>A	p.Met119Ile	missense	Exon 3 of 4	NP_001294859.1	Q9NYN1-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RASL12	ENST00000220062.9	TSL:1 MANE Select	c.414G>A	p.Met138Ile	missense	Exon 4 of 5	ENSP00000220062.4	Q9NYN1-1
RASL12	ENST00000434605.2	TSL:2	c.381G>A	p.Met127Ile	missense	Exon 4 of 5	ENSP00000412787.2	Q9NYN1-2
RASL12	ENST00000421977.7	TSL:2	c.357G>A	p.Met119Ile	missense	Exon 3 of 4	ENSP00000390028.3	Q9NYN1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000133

AC:

AN:

225376

AF XY:

0.0000248

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000171

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1412898

Hom.:

Cov.:

AF XY:

0.00000431

AC XY:

AN XY:

696792

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32616

American (AMR)

AF:

0.00

AC:

AN:

41590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23872

East Asian (EAS)

AF:

0.000104

AC:

AN:

38632

South Asian (SAS)

AF:

0.00

AC:

AN:

79144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081198

Other (OTH)

AF:

0.00

AC:

AN:

58222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

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

Pathogenic

0.93

BayesDel_addAF

Benign

-0.00086

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.5

PhyloP100

7.1

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.62

Sift

Benign

0.034

Sift4G

Uncertain

0.055

Polyphen

0.24

Vest4

0.80

MutPred

0.78

Gain of methylation at K135 (P = 0.0753)

MVP

0.83

MPC

0.26

ClinPred

0.53

GERP RS

5.2

Varity_R

0.57

gMVP

0.61

Mutation Taster

=20/80

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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