17-40191419-C-T

Variant names:

• chr17-40191419-C-T
• rs1990260088
• NM_016339.6:c.1439C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016339.6(RAPGEFL1):​c.1439C>T​(p.Ala480Val) 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RAPGEFL1 NM_016339.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22430605).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEFL1	NM_016339.6	c.1439C>T	p.Ala480Val	missense_variant	Exon 9 of 15	ENST00000620260.6	NP_057423.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEFL1	ENST00000620260.6	c.1439C>T	p.Ala480Val	missense_variant	Exon 9 of 15	1	NM_016339.6	ENSP00000479735.1
RAPGEFL1	ENST00000456989.6	c.986C>T	p.Ala329Val	missense_variant	Exon 9 of 15	1		ENSP00000394530.2
RAPGEFL1	ENST00000544503.5	c.968C>T	p.Ala323Val	missense_variant	Exon 9 of 15	2		ENSP00000438631.1
RAPGEFL1	ENST00000264644.10	c.821C>T	p.Ala274Val	missense_variant	Exon 9 of 15	5		ENSP00000264644.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452534 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 722554

Gnomad4 AFR exome AF: 0.00

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.821C>T (p.A274V) alteration is located in exon 9 (coding exon 7) of the RAPGEFL1 gene. This alteration results from a C to T substitution at nucleotide position 821, causing the alanine (A) at amino acid position 274 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	Benign	0.28
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.0097	.;T;.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.69	N;N;.;.
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;.;.
Sift4G	Benign	0.15	T;T;T;T
Vest4		0.36
MutPred		0.54		.;.;.;Loss of catalytic residue at A480 (P = 0.3572);
MVP		0.15
ClinPred		0.84	D
GERP RS		5.0
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs1990260088; hg19: chr17-38347671;