5-131430969-T-G

Position:

• chr5-131430969-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016340.6(RAPGEF6):​c.4355A>C​(p.Gln1452Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1452R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RAPGEF6 NM_016340.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1581457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF6	NM_016340.6	c.4355A>C	p.Gln1452Pro	missense_variant	26/28	ENST00000509018.6	NP_057424.3
RAPGEF6	NM_001164386.2	c.4379A>C	p.Gln1460Pro	missense_variant	27/29		NP_001157858.1
RAPGEF6	NM_001164387.2	c.4394A>C	p.Gln1465Pro	missense_variant	28/29		NP_001157859.1
RAPGEF6	NM_001164388.2	c.4379A>C	p.Gln1460Pro	missense_variant	27/28		NP_001157860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF6	ENST00000509018.6	c.4355A>C	p.Gln1452Pro	missense_variant	26/28	1	NM_016340.6	ENSP00000421684.1
ENSG00000273217	ENST00000514667.1	c.4505A>C	p.Gln1502Pro	missense_variant	27/29	2		ENSP00000426948.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;T;D;T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N;.;N;.;N
REVEL	Benign	0.095
Sift	Uncertain	0.0010	D;.;D;.;D
Sift4G	Uncertain	0.047	D;D;D;D;D
Polyphen		0.0020	B;B;.;.;.
Vest4		0.26
MutPred		0.30		.;.;.;.;Loss of sheet (P = 0.0315);
MVP		0.22
MPC		0.20, 0.20
ClinPred		0.60	D
GERP RS		5.2
Varity_R		0.34
gMVP		0.69

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: rs1291602; hg19: chr5-130766662;