NM_153615.2:c.1133T>C

Variant names:

• chr22-23696660-T-C
• rs1007298
• NM_153615.2:c.1133T>C

Variant summary

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

The NM_153615.2(RGL4):​c.1133T>C​(p.Val378Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,612,944 control chromosomes in the GnomAD database, including 401,077 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.75 (43734 hom., cov: 32)
  • Exomes 𝑓: 0.70 (357343 hom.)
• Consequence: RGL4 NM_153615.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.872
• Publications: 33 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=7.928761E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.88 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.1133T>C	p.Val378Ala	missense	Exon 7 of 11	NP_705843.1	Q8IZJ4-1
	RGL4	NM_001329424.3		c.1133T>C	p.Val378Ala	missense	Exon 7 of 12	NP_001316353.1
	RGL4	NM_001329425.2		c.-5T>C		5_prime_UTR	Exon 2 of 6	NP_001316354.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGL4	ENST00000290691.10	TSL:1 MANE Select	c.1133T>C	p.Val378Ala	missense	Exon 7 of 11	ENSP00000290691.5	Q8IZJ4-1
	RGL4	ENST00000423392.5	TSL:1	c.1133T>C	p.Val378Ala	missense	Exon 7 of 12	ENSP00000402142.1	E7EPT8
	RGL4	ENST00000441897.5	TSL:2	n.1300T>C		non_coding_transcript_exon	Exon 10 of 14	ENSP00000396252.1	E9PH21

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114473 AN: 151968 Hom.: 43680 Cov.: 32

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.770

Gnomad ASJ AF: 0.774

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.751

GnomAD2 exomes AF: 0.716 AC: 178895 AN: 249848 AF XY: 0.712

Gnomad AFR exome AF: 0.890

Gnomad AMR exome AF: 0.759

Gnomad ASJ exome AF: 0.764

Gnomad EAS exome AF: 0.676

Gnomad FIN exome AF: 0.674

Gnomad NFE exome AF: 0.682

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.698 AC: 1019818 AN: 1460858 Hom.: 357343 Cov.: 49 AF XY: 0.699 AC XY: 508084 AN XY: 726760

African (AFR) AF: 0.894 AC: 29890 AN: 33450

American (AMR) AF: 0.762 AC: 34022 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 20023 AN: 26114

East Asian (EAS) AF: 0.696 AC: 27610 AN: 39690

South Asian (SAS) AF: 0.740 AC: 63834 AN: 86224

European-Finnish (FIN) AF: 0.668 AC: 35628 AN: 53308

Middle Eastern (MID) AF: 0.756 AC: 4186 AN: 5534

European-Non Finnish (NFE) AF: 0.685 AC: 761288 AN: 1111534

Other (OTH) AF: 0.718 AC: 43337 AN: 60330

GnomAD4 genome AF: 0.753 AC: 114587 AN: 152086 Hom.: 43734 Cov.: 32 AF XY: 0.753 AC XY: 55968 AN XY: 74340

African (AFR) AF: 0.888 AC: 36877 AN: 41526

American (AMR) AF: 0.771 AC: 11783 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.774 AC: 2687 AN: 3470

East Asian (EAS) AF: 0.690 AC: 3538 AN: 5130

South Asian (SAS) AF: 0.746 AC: 3596 AN: 4822

European-Finnish (FIN) AF: 0.681 AC: 7210 AN: 10590

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46486 AN: 67948

Other (OTH) AF: 0.752 AC: 1587 AN: 2110

Alfa AF: 0.704 Hom.: 158420

Bravo AF: 0.763

TwinsUK AF: 0.683 AC: 2532

ALSPAC AF: 0.691 AC: 2665

ESP6500AA AF: 0.891 AC: 3925

ESP6500EA AF: 0.691 AC: 5944

ExAC AF: 0.715 AC: 86785

Asia WGS AF: 0.706 AC: 2457 AN: 3478

EpiCase AF: 0.693

EpiControl AF: 0.694

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.0
DANN	Benign	0.88
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	7.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.87
PrimateAI	Benign	0.39	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.047
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.095
MPC		0.089
ClinPred		0.0068	T
GERP RS		-0.41
PromoterAI		0.047	Neutral
Varity_R		0.034
gMVP		0.066
Mutation Taster		=99/1	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: rs1007298; hg19: chr22-24038847; COSMIC: COSV51944756; COSMIC: COSV51944756;