18-9517258-G-C

Position:

• chr18-9517258-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006788.4(RALBP1):​c.658G>C​(p.Val220Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: RALBP1 NM_006788.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

Genes affected

RALBP1 (HGNC:9841): (ralA binding protein 1) RALBP1 plays a role in receptor-mediated endocytosis and is a downstream effector of the small GTP-binding protein RAL (see RALA; MIM 179550). Small G proteins, such as RAL, have GDP-bound inactive and GTP-bound active forms, which shift from the inactive to the active state through the action of RALGDS (MIM 601619), which in turn is activated by RAS (see HRAS; MIM 190020) (summary by Feig, 2003 [PubMed 12888294]).[supplied by OMIM, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1891227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALBP1	NM_006788.4	c.658G>C	p.Val220Leu	missense_variant	3/10	ENST00000383432.8	NP_006779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALBP1	ENST00000383432.8	c.658G>C	p.Val220Leu	missense_variant	3/10	1	NM_006788.4	ENSP00000372924.3
RALBP1	ENST00000019317.8	c.658G>C	p.Val220Leu	missense_variant	3/10	1		ENSP00000019317.4
RALBP1	ENST00000609094.2	c.658G>C	p.Val220Leu	missense_variant	3/3	2		ENSP00000492511.1
RALBP1	ENST00000458039.3	c.*37G>C		downstream_gene_variant		3		ENSP00000411556.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.658G>C (p.V220L) alteration is located in exon 3 (coding exon 2) of the RALBP1 gene. This alteration results from a G to C substitution at nucleotide position 658, causing the valine (V) at amino acid position 220 to be replaced by a leucine (L). 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	0.25
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.76
DEOGEN2	Benign	0.10	T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	.;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.89	L;.;L
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.090	N;.;N
REVEL	Benign	0.14
Sift	Benign	0.69	T;.;T
Sift4G	Benign	0.24	T;.;T
Polyphen		0.0010	B;.;B
Vest4		0.50
MutPred		0.65		Loss of methylation at K222 (P = 0.0687);Loss of methylation at K222 (P = 0.0687);Loss of methylation at K222 (P = 0.0687);
MVP		0.082
MPC		0.49
ClinPred		0.64	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.30

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.

Other links and lift over

hg19: chr18-9517256;