17-40184645-G-A

Variant names:

• chr17-40184645-G-A
• rs199502613
• NM_016339.6:c.800G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016339.6(RAPGEFL1):​c.800G>A​(p.Arg267Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,592,866 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: RAPGEFL1 NM_016339.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06501296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEFL1	NM_016339.6	c.800G>A	p.Arg267Lys	missense_variant	Exon 4 of 15	ENST00000620260.6	NP_057423.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEFL1	ENST00000620260.6	c.800G>A	p.Arg267Lys	missense_variant	Exon 4 of 15	1	NM_016339.6	ENSP00000479735.1
RAPGEFL1	ENST00000456989.6	c.347G>A	p.Arg116Lys	missense_variant	Exon 4 of 15	1		ENSP00000394530.2
RAPGEFL1	ENST00000544503.5	c.329G>A	p.Arg110Lys	missense_variant	Exon 4 of 15	2		ENSP00000438631.1
RAPGEFL1	ENST00000264644.10	c.182G>A	p.Arg61Lys	missense_variant	Exon 4 of 15	5		ENSP00000264644.5
RAPGEFL1	ENST00000543876.5	c.182G>A	p.Arg61Lys	missense_variant	Exon 4 of 6	4		ENSP00000440226.1
RAPGEFL1	ENST00000538981.1	c.182G>A	p.Arg61Lys	missense_variant	Exon 3 of 4	2		ENSP00000441059.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152110 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000562 AC: 13 AN: 231328 Hom.: 0 AF XY: 0.0000639 AC XY: 8 AN XY: 125266

Gnomad AFR exome AF: 0.0000701

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000134 AC: 193 AN: 1440756 Hom.: 1 Cov.: 30 AF XY: 0.000130 AC XY: 93 AN XY: 716306

Gnomad4 AFR exome AF: 0.000121

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: 0.000170

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152110 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 8 AN XY: 74296

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.182G>A (p.R61K) alteration is located in exon 4 (coding exon 2) of the RAPGEFL1 gene. This alteration results from a G to A substitution at nucleotide position 182, causing the arginine (R) at amino acid position 61 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	0.096
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0020	.;T;T;.;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	0.00017
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.71	T;T;T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.065	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.47	N;N;N;N;.;N
REVEL	Benign	0.058
Sift	Benign	0.93	T;T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Vest4		0.16
MVP		0.043
ClinPred		0.064	T
GERP RS		4.2
gMVP		0.16

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: rs199502613; hg19: chr17-38340897;