4-52862582-T-G

Variant names:

• chr4-52862582-T-G
• rs1718179785
• NM_023940.3:c.75T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_023940.3(RASL11B):​c.75T>G​(p.Cys25Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,449,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RASL11B NM_023940.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0710

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30861115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RASL11B	NM_023940.3	c.75T>G	p.Cys25Trp	missense_variant	Exon 1 of 4	ENST00000248706.5	NP_076429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RASL11B	ENST00000248706.5	c.75T>G	p.Cys25Trp	missense_variant	Exon 1 of 4	1	NM_023940.3	ENSP00000248706.3
RASL11B	ENST00000515677.1	n.251T>G		non_coding_transcript_exon_variant	Exon 1 of 2	3
LINC01618	ENST00000650700.1	n.989-686T>G		intron_variant	Intron 8 of 10
LINC01618	ENST00000652441.1	n.504-686T>G		intron_variant	Intron 3 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1449718 Hom.: 0 Cov.: 32 AF XY: 0.00000555 AC XY: 4 AN XY: 720994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.75T>G (p.C25W) alteration is located in exon 1 (coding exon 1) of the RASL11B gene. This alteration results from a T to G substitution at nucleotide position 75, causing the cysteine (C) at amino acid position 25 to be replaced by a tryptophan (W). 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	Benign	0.31
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Benign	0.18	T
Sift4G	Benign	0.066	T
Polyphen		0.95	P
Vest4		0.53
MutPred		0.42		Gain of MoRF binding (P = 0.0155);
MVP		0.24
MPC		0.85
ClinPred		0.23	T
GERP RS		-0.26
Varity_R		0.18
gMVP		0.58

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

Other links and lift over

dbSNP: rs1718179785; hg19: chr4-53728749;