5-131430969-T-C

Variant names:

• chr5-131430969-T-C
• rs1291602
• NM_016340.6:c.4355A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016340.6(RAPGEF6):​c.4355A>G​(p.Gln1452Arg) variant causes a missense change. The variant allele was found at a frequency of 0.851 in 1,614,014 control chromosomes in the GnomAD database, including 585,619 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.88 (59089 hom., cov: 31)
  • Exomes 𝑓: 0.85 (526530 hom.)
• Consequence: RAPGEF6 NM_016340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83
• Publications: 43 publications found

Genes affected

RAPGEF6 (HGNC:20655): (Rap guanine nucleotide exchange factor 6) Enables several functions, including GTP-dependent protein binding activity; guanyl-nucleotide exchange factor activity; and phosphatidic acid binding activity. Involved in microvillus assembly; positive regulation of GTPase activity; and protein localization to plasma membrane. Located in several cellular components, including apical plasma membrane; centrosome; and endocytic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000273217 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.6677055E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016340.6. 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
	RAPGEF6	NM_016340.6	MANE Select	c.4355A>G	p.Gln1452Arg	missense	Exon 26 of 28	NP_057424.3	Q8TEU7-1
	RAPGEF6	NM_001164386.2		c.4379A>G	p.Gln1460Arg	missense	Exon 27 of 29	NP_001157858.1	Q8TEU7-4
	RAPGEF6	NM_001164387.2		c.4394A>G	p.Gln1465Arg	missense	Exon 28 of 29	NP_001157859.1	Q8TEU7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPGEF6	ENST00000509018.6	TSL:1 MANE Select	c.4355A>G	p.Gln1452Arg	missense	Exon 26 of 28	ENSP00000421684.1	Q8TEU7-1
	ENSG00000273217	ENST00000514667.1	TSL:2	c.4505A>G	p.Gln1502Arg	missense	Exon 27 of 29	ENSP00000426948.1	E9PCH4
	RAPGEF6	ENST00000296859.10	TSL:1	c.4379A>G	p.Gln1460Arg	missense	Exon 27 of 29	ENSP00000296859.6	Q8TEU7-4

Frequencies

GnomAD3 genomes AF: 0.879 AC: 133683 AN: 152076 Hom.: 59027 Cov.: 31

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.903

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.853

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.867

GnomAD2 exomes AF: 0.861 AC: 216554 AN: 251422 AF XY: 0.857

Gnomad AFR exome AF: 0.964

Gnomad AMR exome AF: 0.891

Gnomad ASJ exome AF: 0.893

Gnomad EAS exome AF: 0.888

Gnomad FIN exome AF: 0.826

Gnomad NFE exome AF: 0.838

Gnomad OTH exome AF: 0.853

GnomAD4 exome AF: 0.848 AC: 1240178 AN: 1461820 Hom.: 526530 Cov.: 66 AF XY: 0.848 AC XY: 616505 AN XY: 727208

African (AFR) AF: 0.962 AC: 32211 AN: 33476

American (AMR) AF: 0.892 AC: 39876 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.892 AC: 23316 AN: 26134

East Asian (EAS) AF: 0.901 AC: 35776 AN: 39694

South Asian (SAS) AF: 0.860 AC: 74179 AN: 86256

European-Finnish (FIN) AF: 0.827 AC: 44182 AN: 53416

Middle Eastern (MID) AF: 0.816 AC: 4703 AN: 5766

European-Non Finnish (NFE) AF: 0.840 AC: 934044 AN: 1111970

Other (OTH) AF: 0.859 AC: 51891 AN: 60388

GnomAD4 genome AF: 0.879 AC: 133803 AN: 152194 Hom.: 59089 Cov.: 31 AF XY: 0.878 AC XY: 65358 AN XY: 74398

African (AFR) AF: 0.961 AC: 39933 AN: 41542

American (AMR) AF: 0.883 AC: 13502 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3106 AN: 3472

East Asian (EAS) AF: 0.890 AC: 4604 AN: 5172

South Asian (SAS) AF: 0.852 AC: 4114 AN: 4826

European-Finnish (FIN) AF: 0.818 AC: 8642 AN: 10562

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.838 AC: 57015 AN: 68010

Other (OTH) AF: 0.865 AC: 1830 AN: 2116

Alfa AF: 0.855 Hom.: 116016

Bravo AF: 0.891

TwinsUK AF: 0.845 AC: 3135

ALSPAC AF: 0.839 AC: 3232

ESP6500AA AF: 0.960 AC: 4231

ESP6500EA AF: 0.842 AC: 7240

ExAC AF: 0.860 AC: 104390

Asia WGS AF: 0.861 AC: 2993 AN: 3478

EpiCase AF: 0.838

EpiControl AF: 0.841

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	5.7e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.0	N
PhyloP100		4.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.95	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.18
ClinPred		0.0089	T
GERP RS		5.2
Varity_R		0.050
gMVP		0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs1291602; hg19: chr5-130766662; COSMIC: COSV107333966; COSMIC: COSV107333966;