Genetic Variant RASL11B:p.His158Pro (chr4-52865531-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_023940.3(RASL11B):c.473A>C(p.His158Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RASL11B
NM_023940.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.94

Variant links:

Genes affected

RASL11B (HGNC:23804): (RAS like family 11 member B) Predicted to enable G protein activity; GTP binding activity; and transforming growth factor beta receptor binding activity. Predicted to act upstream of or within negative regulation of transforming growth factor beta receptor signaling pathway. [provided by Alliance of Genome Resources, Apr 2022]

RASL11B links:

LINC01618 (HGNC:27195): (long intergenic non-protein coding RNA 1618)

LINC01618 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASL11B	NM_023940.3 link	c.473A>C	p.His158Pro	missense_variant	Exon 4 of 4	ENST00000248706.5	NP_076429.1	Q9BPW5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RASL11B	ENST00000248706.5 link	c.473A>C	p.His158Pro	missense_variant	Exon 4 of 4	1	NM_023940.3	ENSP00000248706.3	Q9BPW5
RASL11B	ENST00000505041.1 link	n.465A>C		non_coding_transcript_exon_variant	Exon 3 of 3	3
LINC01618	ENST00000650700.1 link	n.1319A>C		non_coding_transcript_exon_variant	Exon 11 of 11
LINC01618	ENST00000652441.1 link	n.834A>C		non_coding_transcript_exon_variant	Exon 6 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.473A>C (p.H158P) alteration is located in exon 4 (coding exon 4) of the RASL11B gene. This alteration results from a A to C substitution at nucleotide position 473, causing the histidine (H) at amino acid position 158 to be replaced by a proline (P). 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

0.73

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-8.3

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.76

MutPred

0.43

Gain of methylation at K153 (P = 0.0766);

MVP

0.89

MPC

1.2

ClinPred

0.99

GERP RS

5.6

Varity_R

0.88

gMVP

0.70

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over