chr5-131431160-C-A

Variant names:

• chr5-131431160-C-A
• rs754049684
• NM_016340.6:c.4164G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016340.6(RAPGEF6):​c.4164G>T​(p.Leu1388Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAPGEF6 NM_016340.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0200
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1615574).

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.4164G>T	p.Leu1388Phe	missense	Exon 26 of 28	NP_057424.3	Q8TEU7-1
	RAPGEF6	NM_001164386.2		c.4188G>T	p.Leu1396Phe	missense	Exon 27 of 29	NP_001157858.1	Q8TEU7-4
	RAPGEF6	NM_001164387.2		c.4203G>T	p.Leu1401Phe	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.4164G>T	p.Leu1388Phe	missense	Exon 26 of 28	ENSP00000421684.1	Q8TEU7-1
	ENSG00000273217	ENST00000514667.1	TSL:2	c.4314G>T	p.Leu1438Phe	missense	Exon 27 of 29	ENSP00000426948.1	E9PCH4
	RAPGEF6	ENST00000296859.10	TSL:1	c.4188G>T	p.Leu1396Phe	missense	Exon 27 of 29	ENSP00000296859.6	Q8TEU7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250534 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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	0.099
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.020
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.047	D
Polyphen		0.98	D
Vest4		0.15
MutPred		0.15		Loss of stability (P = 0.1105)
MVP		0.31
MPC		0.19
ClinPred		0.51	D
GERP RS		3.3
Varity_R		0.11
gMVP		0.17
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs754049684; hg19: chr5-130766853;