9-133098651-C-G

Position:

• chr9-133098651-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000372050.8(RALGDS):​c.2681G>C​(p.Gly894Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G894R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RALGDS ENST00000372050.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

Genes affected

RALGDS (HGNC:9842): (ral guanine nucleotide dissociation stimulator) Guanine nucleotide dissociation stimulators (GDSs, or exchange factors), such as RALGDS, are effectors of Ras-related GTPases (see MIM 190020) that participate in signaling for a variety of cellular processes.[supplied by OMIM, Nov 2010]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12564528).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RALGDS	NM_006266.4	c.2681G>C	p.Gly894Ala	missense_variant	18/18	ENST00000372050.8	NP_006257.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RALGDS	ENST00000372050.8	c.2681G>C	p.Gly894Ala	missense_variant	18/18	1	NM_006266.4	ENSP00000361120	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461878 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727240

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Mar 29, 2022

The c.2681G>C (p.G894A) alteration is located in exon 18 (coding exon 18) of the RALGDS gene. This alteration results from a G to C substitution at nucleotide position 2681, causing the glycine (G) at amino acid position 894 to be replaced by an alanine (A). 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	0.11
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.095
DEOGEN2	Benign	0.17	T;.;.;.;.;.
Eigen	Benign	-0.0041
Eigen_PC	Benign	0.025
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.
MutationTaster	Benign	0.93	D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.96	N;N;N;N;N;.
REVEL	Benign	0.055
Sift	Benign	0.44	T;T;T;T;T;.
Sift4G	Benign	0.73	T;T;T;T;T;.
Polyphen		0.11	B;.;.;.;.;.
Vest4		0.25
MVP		0.60
MPC		0.34
ClinPred		0.55	D
GERP RS		4.5
Varity_R		0.15
gMVP		0.28

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: rs1743006719; hg19: chr9-135974038;