chrX-55722192-T-A

Variant names:

• chrX-55722192-T-A
• rs765547725
• NM_006064.5:c.133T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006064.5(RRAGB):​c.133T>A​(p.Leu45Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,175,602 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: RRAGB NM_006064.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64
• Publications: 0 publications found

Genes affected

RRAGB (HGNC:19901): (Ras related GTP binding B) Ras-homologous GTPases constitute a large family of signal transducers that alternate between an activated, GTP-binding state and an inactivated, GDP-binding state. These proteins represent cellular switches that are operated by GTP-exchange factors and factors that stimulate their intrinsic GTPase activity. All GTPases of the Ras superfamily have in common the presence of six conserved motifs involved in GTP/GDP binding, three of which are phosphate-/magnesium-binding sites (PM1-PM3) and three of which are guanine nucleotide-binding sites (G1-G3). Transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RRAGB	NM_006064.5	c.133T>A	p.Leu45Met	missense_variant	Exon 3 of 10	ENST00000374941.9	NP_006055.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RRAGB	ENST00000374941.9	c.133T>A	p.Leu45Met	missense_variant	Exon 3 of 10	1	NM_006064.5	ENSP00000364077.4
RRAGB	ENST00000262850.7	c.133T>A	p.Leu45Met	missense_variant	Exon 3 of 11	1		ENSP00000262850.7
RRAGB	ENST00000414239.5	c.19T>A	p.Leu7Met	missense_variant	Exon 3 of 7	5		ENSP00000410630.1
RRAGB	ENST00000498762.1	n.2T>A		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.00000887 AC: 1 AN: 112678 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000277

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000276 AC: 5 AN: 181290 AF XY: 0.0000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000364

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000282 AC: 3 AN: 1062872 Hom.: 0 Cov.: 24 AF XY: 0.00000299 AC XY: 1 AN XY: 334294

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25879

American (AMR) AF: 0.00 AC: 0 AN: 34889

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18842

East Asian (EAS) AF: 0.000100 AC: 3 AN: 29870

South Asian (SAS) AF: 0.00 AC: 0 AN: 51237

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4020

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 813724

Other (OTH) AF: 0.00 AC: 0 AN: 44597

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112730 Hom.: 0 Cov.: 24 AF XY: 0.0000573 AC XY: 2 AN XY: 34884

African (AFR) AF: 0.00 AC: 0 AN: 31065

American (AMR) AF: 0.00 AC: 0 AN: 10719

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.000556 AC: 2 AN: 3598

South Asian (SAS) AF: 0.00 AC: 0 AN: 2728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6215

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53311

Other (OTH) AF: 0.00 AC: 0 AN: 1536

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133T>A (p.L45M) alteration is located in exon 3 (coding exon 3) of the RRAGB gene. This alteration results from a T to A substitution at nucleotide position 133, causing the leucine (L) at amino acid position 45 to be replaced by a methionine (M). 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	0.92
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;.;T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Uncertain	-0.054	T
MutationAssessor	Pathogenic	3.9	H;.;H
PhyloP100		1.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.62
MutPred		0.70		Gain of disorder (P = 0.0662);.;Gain of disorder (P = 0.0662);
MVP		0.88
MPC		1.8
ClinPred		0.93	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.90
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs765547725; hg19: chrX-55748625;