chr17-40184645-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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. 13/20 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
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06501296).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016339.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEFL1	NM_016339.6	MANE Select	c.800G>A	p.Arg267Lys	missense	Exon 4 of 15	NP_057423.2	A0A087WVW6
	RAPGEFL1	NM_001303533.2		c.347G>A	p.Arg116Lys	missense	Exon 4 of 15	NP_001290462.1	Q9UHV5-3
	RAPGEFL1	NM_001303534.3		c.329G>A	p.Arg110Lys	missense	Exon 4 of 15	NP_001290463.1	F5H2D5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEFL1	ENST00000620260.6	TSL:1 MANE Select	c.800G>A	p.Arg267Lys	missense	Exon 4 of 15	ENSP00000479735.1	A0A087WVW6
	RAPGEFL1	ENST00000456989.6	TSL:1	c.347G>A	p.Arg116Lys	missense	Exon 4 of 15	ENSP00000394530.2	Q9UHV5-3
	RAPGEFL1	ENST00000544503.5	TSL:2	c.329G>A	p.Arg110Lys	missense	Exon 4 of 15	ENSP00000438631.1	F5H2D5

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

GnomAD2 exomes AF: 0.0000562 AC: 13 AN: 231328 AF XY: 0.0000639

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 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

African (AFR) AF: 0.000121 AC: 4 AN: 33068

American (AMR) AF: 0.00 AC: 0 AN: 43320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 39362

South Asian (SAS) AF: 0.00 AC: 0 AN: 84248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52672

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.000170 AC: 187 AN: 1097016

Other (OTH) AF: 0.0000335 AC: 2 AN: 59638

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

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000161 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.22
Eigen_PC	Benign	0.00017
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.058
Sift	Benign	0.93	T
Sift4G	Benign	1.0	T
Vest4		0.16
MVP		0.043
ClinPred		0.064	T
GERP RS		4.2
gMVP		0.16
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs199502613; hg19: chr17-38340897;