rs758022116

chr20-38535152-G-Achr20-38535152-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_020336.4(RALGAPB):c.2324G>A(p.Arg775His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R775L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RALGAPB NM_020336.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.63

Genes affected

RALGAPB (HGNC:29221): (Ral GTPase activating protein non-catalytic subunit beta) Enables protein heterodimerization activity. Predicted to be involved in activation of GTPase activity. Predicted to act upstream of or within Ral protein signal transduction; regulation of exocyst localization; and regulation of protein localization. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr20-38535152-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370037.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, RALGAPB

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RALGAPB	NM_020336.4	c.2324G>A	p.Arg775His	missense_variant	16/30	ENST00000262879.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RALGAPB	ENST00000262879.11	c.2324G>A	p.Arg775His	missense_variant	16/30	1	NM_020336.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727218

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.3	N;N;N;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		1.0, 1.0	.;D;D;D
Vest4		0.74
MutPred		0.26		.;Loss of MoRF binding (P = 0.0145);Loss of MoRF binding (P = 0.0145);.;
MVP		0.40
MPC		1.4
ClinPred		0.87	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.23
gMVP		0.44

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: rs758022116; hg19: chr20-37163795;