chr5-131431044-C-T

Variant names:

• chr5-131431044-C-T
• NM_016340.6:c.4280G>A

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.4280G>A​(p.Ser1427Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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)
• Consequence: RAPGEF6 NM_016340.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08
• 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=0.090421766).

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.4280G>A	p.Ser1427Asn	missense	Exon 26 of 28	NP_057424.3	Q8TEU7-1
	RAPGEF6	NM_001164386.2		c.4304G>A	p.Ser1435Asn	missense	Exon 27 of 29	NP_001157858.1	Q8TEU7-4
	RAPGEF6	NM_001164387.2		c.4319G>A	p.Ser1440Asn	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.4280G>A	p.Ser1427Asn	missense	Exon 26 of 28	ENSP00000421684.1	Q8TEU7-1
	ENSG00000273217	ENST00000514667.1	TSL:2	c.4430G>A	p.Ser1477Asn	missense	Exon 27 of 29	ENSP00000426948.1	E9PCH4
	RAPGEF6	ENST00000296859.10	TSL:1	c.4304G>A	p.Ser1435Asn	missense	Exon 27 of 29	ENSP00000296859.6	Q8TEU7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

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	0.065
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.028
Sift	Benign	0.14	T
Sift4G	Benign	0.89	T
Polyphen		0.0050	B
Vest4		0.065
MutPred		0.13		Loss of phosphorylation at S1477 (P = 0.017)
MVP		0.26
MPC		0.15
ClinPred		0.14	T
GERP RS		2.4
Varity_R		0.031
gMVP		0.26
Mutation Taster		=97/3	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

hg19: chr5-130766737;