15-65058438-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.11
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RASL12NM_016563.4 linkc.414G>A p.Met138Ile missense_variant Exon 4 of 5 ENST00000220062.9 NP_057647.1 Q9NYN1-1A0A024R5Y3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RASL12ENST00000220062.9 linkc.414G>A p.Met138Ile missense_variant Exon 4 of 5 1 NM_016563.4 ENSP00000220062.4 Q9NYN1-1
RASL12ENST00000434605.2 linkc.381G>A p.Met127Ile missense_variant Exon 4 of 5 2 ENSP00000412787.2 Q9NYN1-2
RASL12ENST00000421977.7 linkc.357G>A p.Met119Ile missense_variant Exon 3 of 4 2 ENSP00000390028.3 Q9NYN1-3

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.0000133
AC:
3
AN:
225376
Hom.:
0
AF XY:
0.0000248
AC XY:
3
AN XY:
120810
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 SAS 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:
0.00000283
AC:
4
AN:
1412898
Hom.:
0
Cov.:
35
AF XY:
0.00000431
AC XY:
3
AN XY:
696792
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000104
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 31, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.414G>A (p.M138I) alteration is located in exon 4 (coding exon 4) of the RASL12 gene. This alteration results from a G to A substitution at nucleotide position 414, causing the methionine (M) at amino acid position 138 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Benign
-0.00086
T
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
T;.;.
Eigen
Uncertain
0.21
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.89
D;D;D
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
1.5
L;.;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Uncertain
0.62
Sift
Benign
0.034
D;D;D
Sift4G
Uncertain
0.055
T;T;T
Polyphen
0.24
B;.;.
Vest4
0.80
MutPred
0.78
Gain of methylation at K135 (P = 0.0753);.;.;
MVP
0.83
MPC
0.26
ClinPred
0.53
D
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs760634539; hg19: chr15-65350776; API