20-38488469-C-G

Position:

• chr20-38488469-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_020336.4(RALGAPB):​c.37C>G​(p.Gln13Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RALGAPB NM_020336.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RALGAPB. . Gene score misZ 3.1771 (greater than the threshold 3.09). Trascript score misZ 4.2843 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18702888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGAPB	NM_020336.4	c.37C>G	p.Gln13Glu	missense_variant	2/30	ENST00000262879.11	NP_065069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGAPB	ENST00000262879.11	c.37C>G	p.Gln13Glu	missense_variant	2/30	1	NM_020336.4	ENSP00000262879.6
RALGAPB	ENST00000397040.5	c.37C>G	p.Gln13Glu	missense_variant	2/30	1		ENSP00000380233.1
RALGAPB	ENST00000397042.7	c.37C>G	p.Gln13Glu	missense_variant	2/30	1		ENSP00000380235.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 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

May 10, 2023

The c.37C>G (p.Q13E) alteration is located in exon 2 (coding exon 1) of the RALGAPB gene. This alteration results from a C to G substitution at nucleotide position 37, causing the glutamine (Q) at amino acid position 13 to be replaced by a glutamic acid (E). 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	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.031	.;T;T
Eigen	Benign	-0.041
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L;L;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.92	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.17	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0030	.;B;B
Vest4		0.31
MutPred		0.63		Loss of MoRF binding (P = 0.0755);Loss of MoRF binding (P = 0.0755);Loss of MoRF binding (P = 0.0755);
MVP		0.15
MPC		0.58
ClinPred		0.34	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.18
gMVP		0.56

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: rs1568903092; hg19: chr20-37117112;