17-40184653-C-A

Position:

• chr17-40184653-C-A

Variant summary

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

The NM_016339.6(RAPGEFL1):​c.808C>A​(p.Gln270Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RAPGEFL1 NM_016339.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.53

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=0.1456967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEFL1	NM_016339.6	c.808C>A	p.Gln270Lys	missense_variant	4/15	ENST00000620260.6	NP_057423.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEFL1	ENST00000620260.6	c.808C>A	p.Gln270Lys	missense_variant	4/15	1	NM_016339.6	ENSP00000479735.1
RAPGEFL1	ENST00000456989.6	c.355C>A	p.Gln119Lys	missense_variant	4/15	1		ENSP00000394530.2
RAPGEFL1	ENST00000544503.5	c.337C>A	p.Gln113Lys	missense_variant	4/15	2		ENSP00000438631.1
RAPGEFL1	ENST00000264644.10	c.190C>A	p.Gln64Lys	missense_variant	4/15	5		ENSP00000264644.5
RAPGEFL1	ENST00000543876.5	c.190C>A	p.Gln64Lys	missense_variant	4/6	4		ENSP00000440226.1
RAPGEFL1	ENST00000538981.1	c.190C>A	p.Gln64Lys	missense_variant	3/4	2		ENSP00000441059.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437420 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 714766

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000232

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.: 30

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

Jun 28, 2022

The c.190C>A (p.Q64K) alteration is located in exon 4 (coding exon 2) of the RAPGEFL1 gene. This alteration results from a C to A substitution at nucleotide position 190, causing the glutamine (Q) at amino acid position 64 to be replaced by a lysine (K). 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	0.13
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0025	.;T;T;.;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.0086
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.31	N;N;N;.;.;N
REVEL	Benign	0.17
Sift	Benign	0.72	T;T;T;.;.;T
Sift4G	Benign	0.55	T;T;T;T;T;T
Vest4		0.62
MutPred		0.35		.;.;.;.;Gain of ubiquitination at Q270 (P = 0.0325);.;
MVP		0.043
ClinPred		0.48	T
GERP RS		5.3
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1330182244; hg19: chr17-38340905;