rs1599432341

Variant names:

• chr19-11402065-T-G
• rs1599432341
• NM_001035223.4:c.1430A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001035223.4(RGL3):​c.1430A>C​(p.His477Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: RGL3 NM_001035223.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0730
• Publications: 0 publications found

Genes affected

RGL3 (HGNC:30282): (ral guanine nucleotide dissociation stimulator like 3) Predicted to enable guanyl-nucleotide exchange factor activity and small GTPase binding activity. Predicted to be involved in positive regulation of GTPase activity and small GTPase mediated signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13827765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGL3	NM_001035223.4	c.1430A>C	p.His477Pro	missense_variant	Exon 13 of 19	ENST00000380456.8	NP_001030300.3
RGL3	NM_001161616.3	c.1430A>C	p.His477Pro	missense_variant	Exon 13 of 19		NP_001155088.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGL3	ENST00000380456.8	c.1430A>C	p.His477Pro	missense_variant	Exon 13 of 19	1	NM_001035223.4	ENSP00000369823.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1430A>C (p.H477P) alteration is located in exon 13 (coding exon 13) of the RGL3 gene. This alteration results from a A to C substitution at nucleotide position 1430, causing the histidine (H) at amino acid position 477 to be replaced by a proline (P). 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	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.091
DANN	Benign	0.78
DEOGEN2	Benign	0.034	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.31	T;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.92	T
PhyloP100		0.073
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.13
Sift	Benign	0.045	D;D
Sift4G	Benign	0.090	T;T
Vest4		0.37
MutPred		0.46		Gain of glycosylation at H477 (P = 0.0014);Gain of glycosylation at H477 (P = 0.0014);
MVP		0.13
MPC		0.40
ClinPred		0.19	T
GERP RS		-3.6
gMVP		0.56
Mutation Taster		=89/11	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: rs1599432341; hg19: chr19-11512741;