22-23693783-C-T

Variant names:

• chr22-23693783-C-T
• rs2070446
• NM_153615.2:c.721C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_153615.2(RGL4):​c.721C>T​(p.His241Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 1,613,264 control chromosomes in the GnomAD database, including 418,933 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.77 (46287 hom., cov: 31)
  • Exomes 𝑓: 0.71 (372646 hom.)
• Consequence: RGL4 NM_153615.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77
• Publications: 37 publications found

Genes affected

RGL4 (HGNC:31911): (ral guanine nucleotide dissociation stimulator like 4) This oncogene encodes a protein similar to guanine nucleotide exchange factor Ral guanine dissociation stimulator. Increased expression of this gene leads to translocation of the encoded protein to the cell membrane. The encoded protein can activate several pathways, including the Ras-Raf-MEK-ERK cascade. [provided by RefSeq, Jul 2016]

GUSBP11 (HGNC:):

GUSBP11 (HGNC:42325): (GUSB pseudogene 11) This transcribed pseudogene is similar to two functional genes. The 5' portion of the pseudogene is related to glucuronidase, beta, and the 3' portion is related to immunoglobulin lambda-like polypeptide 1. [provided by RefSeq, Jul 2011]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.5518795E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153615.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGL4	NM_153615.2	MANE Select	c.721C>T	p.His241Tyr	missense	Exon 4 of 11	NP_705843.1	Q8IZJ4-1
	RGL4	NM_001329424.3		c.721C>T	p.His241Tyr	missense	Exon 4 of 12	NP_001316353.1
	GUSBP11	NR_024448.2		n.2561+336G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGL4	ENST00000290691.10	TSL:1 MANE Select	c.721C>T	p.His241Tyr	missense	Exon 4 of 11	ENSP00000290691.5	Q8IZJ4-1
	RGL4	ENST00000423392.5	TSL:1	c.721C>T	p.His241Tyr	missense	Exon 4 of 12	ENSP00000402142.1	E7EPT8
	RGL4	ENST00000441897.5	TSL:2	n.721C>T		non_coding_transcript_exon	Exon 6 of 14	ENSP00000396252.1	E9PH21

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117574 AN: 151928 Hom.: 46234 Cov.: 31

Gnomad AFR AF: 0.925

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.668

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.704

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.768

GnomAD2 exomes AF: 0.729 AC: 183087 AN: 251264 AF XY: 0.724

Gnomad AFR exome AF: 0.928

Gnomad AMR exome AF: 0.767

Gnomad ASJ exome AF: 0.787

Gnomad EAS exome AF: 0.665

Gnomad FIN exome AF: 0.699

Gnomad NFE exome AF: 0.699

Gnomad OTH exome AF: 0.724

GnomAD4 exome AF: 0.713 AC: 1041358 AN: 1461218 Hom.: 372646 Cov.: 49 AF XY: 0.713 AC XY: 518539 AN XY: 726966

African (AFR) AF: 0.933 AC: 31216 AN: 33470

American (AMR) AF: 0.770 AC: 34439 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 20590 AN: 26136

East Asian (EAS) AF: 0.660 AC: 26184 AN: 39696

South Asian (SAS) AF: 0.732 AC: 63101 AN: 86240

European-Finnish (FIN) AF: 0.691 AC: 36875 AN: 53356

Middle Eastern (MID) AF: 0.779 AC: 4493 AN: 5768

European-Non Finnish (NFE) AF: 0.702 AC: 780308 AN: 1111454

Other (OTH) AF: 0.731 AC: 44152 AN: 60378

GnomAD4 genome AF: 0.774 AC: 117687 AN: 152046 Hom.: 46287 Cov.: 31 AF XY: 0.774 AC XY: 57486 AN XY: 74298

African (AFR) AF: 0.925 AC: 38401 AN: 41500

American (AMR) AF: 0.781 AC: 11940 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2756 AN: 3470

East Asian (EAS) AF: 0.668 AC: 3442 AN: 5150

South Asian (SAS) AF: 0.735 AC: 3540 AN: 4816

European-Finnish (FIN) AF: 0.704 AC: 7440 AN: 10562

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47711 AN: 67950

Other (OTH) AF: 0.768 AC: 1622 AN: 2112

Alfa AF: 0.723 Hom.: 161911

Bravo AF: 0.784

TwinsUK AF: 0.697 AC: 2585

ALSPAC AF: 0.707 AC: 2726

ESP6500AA AF: 0.926 AC: 4080

ESP6500EA AF: 0.706 AC: 6073

ExAC AF: 0.729 AC: 88449

Asia WGS AF: 0.693 AC: 2412 AN: 3478

EpiCase AF: 0.711

EpiControl AF: 0.713

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.16
DANN	Benign	0.57
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	7.6e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.89	N
PhyloP100		1.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.072
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.074
MPC		0.086
ClinPred		0.0034	T
GERP RS		-1.1
Varity_R		0.022
gMVP		0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs2070446; hg19: chr22-24035970; COSMIC: COSV107332264; COSMIC: COSV107332264;