chr5-131429006-A-T

Position:

• chr5-131429006-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_016340.6(RAPGEF6):​c.4676T>A​(p.Val1559Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00932 in 1,614,196 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0067 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0096 (78 hom.)
• Consequence: RAPGEF6 NM_016340.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0870

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004093528).
• BP6: Variant 5-131429006-A-T is Benign according to our data. Variant chr5-131429006-A-T is described in ClinVar as [Benign]. Clinvar id is 774633.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF6	NM_016340.6	c.4676T>A	p.Val1559Glu	missense_variant	27/28	ENST00000509018.6	NP_057424.3
RAPGEF6	NM_001164386.2	c.4700T>A	p.Val1567Glu	missense_variant	28/29		NP_001157858.1
RAPGEF6	NM_001164387.2	c.4505-1715T>A		intron_variant			NP_001157859.1
RAPGEF6	NM_001164388.2	c.4490-1715T>A		intron_variant			NP_001157860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF6	ENST00000509018.6	c.4676T>A	p.Val1559Glu	missense_variant	27/28	1	NM_016340.6	ENSP00000421684.1
ENSG00000273217	ENST00000514667.1	c.4826T>A	p.Val1609Glu	missense_variant	28/29	2		ENSP00000426948.1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1023 AN: 152212 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00692 AC: 1741 AN: 251468 Hom.: 12 AF XY: 0.00698 AC XY: 948 AN XY: 135908

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00358

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00517

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00700

GnomAD4 exome AF: 0.00959 AC: 14017 AN: 1461866 Hom.: 78 Cov.: 31 AF XY: 0.00935 AC XY: 6803 AN XY: 727236

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00597

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00791

GnomAD4 genome AF: 0.00672 AC: 1023 AN: 152330 Hom.: 3 Cov.: 31 AF XY: 0.00619 AC XY: 461 AN XY: 74494

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00537

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.0101 Hom.: 7

Bravo AF: 0.00609

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0108 AC: 93

ExAC AF: 0.00768 AC: 932

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.00978

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.2
DANN	Benign	0.40
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.62	T;T;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.010	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.50	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.031	B;.;.
Vest4		0.34
MVP		0.10
MPC		0.29, 0.27
ClinPred		0.0013	T
GERP RS		1.4
Varity_R		0.043
gMVP		0.37

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: rs1064539; hg19: chr5-130764699;