Genetic Variant RASL12:p.Met138Ile (chr15-65058438-C-A) – 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>T(p.Met138Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RASL12
NM_016563.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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, 0.909

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>T	p.Met138Ile	missense	Exon 4 of 5	NP_057647.1	Q9NYN1-1
RASL12	NM_001379429.1		c.381G>T	p.Met127Ile	missense	Exon 4 of 5	NP_001366358.1	Q9NYN1-2
RASL12	NM_001307930.2		c.357G>T	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>T	p.Met138Ile	missense	Exon 4 of 5	ENSP00000220062.4	Q9NYN1-1
RASL12	ENST00000434605.2	TSL:2	c.381G>T	p.Met127Ile	missense	Exon 4 of 5	ENSP00000412787.2	Q9NYN1-2
RASL12	ENST00000421977.7	TSL:2	c.357G>T	p.Met119Ile	missense	Exon 3 of 4	ENSP00000390028.3	Q9NYN1-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1412898

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696792

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:

0.00

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.19

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

0.91

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

0.92

GERP RS

5.2

Varity_R

0.57

gMVP

0.61

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over