chr5-131433466-G-A

Position:

• chr5-131433466-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016340.6(RAPGEF6):​c.3938C>T​(p.Ala1313Val) 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 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 2.08

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06673303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF6	NM_016340.6	c.3938C>T	p.Ala1313Val	missense_variant	25/28	ENST00000509018.6	NP_057424.3
RAPGEF6	NM_001164386.2	c.3962C>T	p.Ala1321Val	missense_variant	26/29		NP_001157858.1
RAPGEF6	NM_001164387.2	c.3977C>T	p.Ala1326Val	missense_variant	27/29		NP_001157859.1
RAPGEF6	NM_001164388.2	c.3962C>T	p.Ala1321Val	missense_variant	26/28		NP_001157860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF6	ENST00000509018.6	c.3938C>T	p.Ala1313Val	missense_variant	25/28	1	NM_016340.6	ENSP00000421684.1
ENSG00000273217	ENST00000514667.1	c.4088C>T	p.Ala1363Val	missense_variant	26/29	2		ENSP00000426948.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461320 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

The c.3962C>T (p.A1321V) alteration is located in exon 26 (coding exon 26) of the RAPGEF6 gene. This alteration results from a C to T substitution at nucleotide position 3962, causing the alanine (A) at amino acid position 1321 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T;.;.;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T;T;T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.067	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.64	N;.;N;.;N
REVEL	Benign	0.060
Sift	Benign	0.18	T;.;T;.;T
Sift4G	Benign	0.35	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.044
MutPred		0.18		.;.;.;.;Loss of helix (P = 0.0237);
MVP		0.16
MPC		0.16, 0.16
ClinPred		0.12	T
GERP RS		5.0
Varity_R		0.044
gMVP		0.13

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: rs1751832370; hg19: chr5-130769159;