17-40193415-T-G

Position:

• chr17-40193415-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016339.6(RAPGEFL1):​c.1862T>G​(p.Leu621Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAPGEFL1 NM_016339.6 missense, splice_region
• Scores: Splicing: ADA: 0.3754
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

Genes affected

RAPGEFL1 (HGNC:17428): (Rap guanine nucleotide exchange factor like 1) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in G protein-coupled receptor signaling pathway and nervous system development. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

RAPGEFL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEFL1	NM_016339.6	c.1862T>G	p.Leu621Arg	missense_variant, splice_region_variant	14/15	ENST00000620260.6	NP_057423.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEFL1	ENST00000620260.6	c.1862T>G	p.Leu621Arg	missense_variant, splice_region_variant	14/15	1	NM_016339.6	ENSP00000479735.1
RAPGEFL1	ENST00000456989.6	c.1409T>G	p.Leu470Arg	missense_variant, splice_region_variant	14/15	1		ENSP00000394530.2
RAPGEFL1	ENST00000544503.5	c.1391T>G	p.Leu464Arg	missense_variant, splice_region_variant	14/15	2		ENSP00000438631.1
RAPGEFL1	ENST00000264644.10	c.1244T>G	p.Leu415Arg	missense_variant, splice_region_variant	14/15	5		ENSP00000264644.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

May 09, 2022

The c.1244T>G (p.L415R) alteration is located in exon 14 (coding exon 12) of the RAPGEFL1 gene. This alteration results from a T to G substitution at nucleotide position 1244, causing the leucine (L) at amino acid position 415 to be replaced by an arginine (R). 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	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	.;T;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-0.95	T
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.4	D;D;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Benign	0.079	T;T;T;D
Vest4		0.77
MutPred		0.65		.;.;.;Gain of MoRF binding (P = 0.0117);
MVP		0.38
ClinPred		0.98	D
GERP RS		4.3
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.38
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38349667;