18-9517296-A-C

Position:

• chr18-9517296-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006788.4(RALBP1):​c.696A>C​(p.Arg232Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 0.319

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALBP1	NM_006788.4	c.696A>C	p.Arg232Ser	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.696A>C	p.Arg232Ser	missense_variant	3/10	1	NM_006788.4	ENSP00000372924.3
RALBP1	ENST00000019317.8	c.696A>C	p.Arg232Ser	missense_variant	3/10	1		ENSP00000019317.4
RALBP1	ENST00000609094.2	c.696A>C	p.Arg232Ser	missense_variant	3/3	2		ENSP00000492511.1

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

Jun 10, 2024

The c.696A>C (p.R232S) alteration is located in exon 3 (coding exon 2) of the RALBP1 gene. This alteration results from a A to C substitution at nucleotide position 696, causing the arginine (R) at amino acid position 232 to be replaced by a serine (S). 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	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	4.4	H;.;H
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.6	D;.;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.0040	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.92		Loss of MoRF binding (P = 0.0259);Loss of MoRF binding (P = 0.0259);Loss of MoRF binding (P = 0.0259);
MVP		0.83
MPC		1.5
ClinPred		1.0	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.93

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: chr18-9517294;