1-183806457-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001297671.3(RGL1):c.110C>T(p.Ala37Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RGL1 NM_001297671.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.41

Genes affected

RGL1 (HGNC:30281): (ral guanine nucleotide dissociation stimulator like 1) Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RGL1	NM_001297671.3	c.110C>T	p.Ala37Val	missense_variant	2/18	ENST00000360851.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RGL1	ENST00000360851.4	c.110C>T	p.Ala37Val	missense_variant	2/18	1	NM_001297671.3	P1
RGL1	ENST00000304685.8	c.215C>T	p.Ala72Val	missense_variant	3/19	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461664 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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

Oct 20, 2023

The c.215C>T (p.A72V) alteration is located in exon 3 (coding exon 2) of the RGL1 gene. This alteration results from a C to T substitution at nucleotide position 215, causing the alanine (A) at amino acid position 72 to be replaced by a valine (V). 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	0.64
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.026	D;D
Sift4G	Benign	0.13	T;T
Polyphen		1.0	.;D
Vest4		0.64
MutPred		0.31		.;Loss of ubiquitination at K40 (P = 0.0992);
MVP		0.34
MPC		0.34
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.26
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1661344482; hg19: chr1-183775591;