rs4996522

Positions:

• chr5-131425777-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016340.6(RAPGEF6):​c.*1489C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 151,900 control chromosomes in the GnomAD database, including 4,328 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (4324 hom., cov: 31)
  • Exomes 𝑓: 0.28 (4 hom.)
• Consequence: RAPGEF6 NM_016340.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.433

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF6	NM_016340.6	c.*1489C>T		3_prime_UTR_variant	28/28	ENST00000509018.6	NP_057424.3
RAPGEF6	NM_001164386.2	c.*1489C>T		3_prime_UTR_variant	29/29		NP_001157858.1
RAPGEF6	NM_001164387.2	c.*1489C>T		3_prime_UTR_variant	29/29		NP_001157859.1
RAPGEF6	NM_001164388.2	c.*1489C>T		3_prime_UTR_variant	28/28		NP_001157860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF6	ENST00000509018	c.*1489C>T		3_prime_UTR_variant	28/28	1	NM_016340.6	ENSP00000421684.1
RAPGEF6	ENST00000671916	c.*1489C>T		3_prime_UTR_variant	18/18			ENSP00000500379.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 34996 AN: 151642 Hom.: 4313 Cov.: 31

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.285 AC: 41 AN: 144 Hom.: 4 Cov.: 0 AF XY: 0.317 AC XY: 26 AN XY: 82

Gnomad4 EAS exome AF: 0.290

Gnomad4 NFE exome AF: 0.167

GnomAD4 genome AF: 0.231 AC: 35041 AN: 151756 Hom.: 4324 Cov.: 31 AF XY: 0.239 AC XY: 17739 AN XY: 74170

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.251

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.486

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.214

Alfa AF: 0.209 Hom.: 3438

Bravo AF: 0.222

Asia WGS AF: 0.368 AC: 1282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.4
DANN	Benign	0.58

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: rs4996522; hg19: chr5-130761470; COSMIC: COSV57242881; COSMIC: COSV57242881;