dbSNP rs150501049: RAPGEF6:p.Ser1371Thr (chr5-131431212-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016340.6(RAPGEF6):c.4112G>C(p.Ser1371Thr) 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 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. S1371N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RAPGEF6
NM_016340.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.69

Variant links:

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]

RAPGEF6 links:

ENSG00000273217 (HGNC:):

ENSG00000273217 links:

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ACMG classification

Classification made for transcript

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=0.16087046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF6	NM_016340.6 link	c.4112G>C	p.Ser1371Thr	missense_variant	Exon 26 of 28	ENST00000509018.6	NP_057424.3	Q8TEU7-1
RAPGEF6	NM_001164386.2 link	c.4136G>C	p.Ser1379Thr	missense_variant	Exon 27 of 29		NP_001157858.1	Q8TEU7-4B2RTU6
RAPGEF6	NM_001164387.2 link	c.4151G>C	p.Ser1384Thr	missense_variant	Exon 28 of 29		NP_001157859.1	Q8TEU7-3
RAPGEF6	NM_001164388.2 link	c.4136G>C	p.Ser1379Thr	missense_variant	Exon 27 of 28		NP_001157860.1	Q8TEU7-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF6	ENST00000509018.6 link	c.4112G>C	p.Ser1371Thr	missense_variant	Exon 26 of 28	1	NM_016340.6	ENSP00000421684.1		Q8TEU7-1
ENSG00000273217	ENST00000514667.1 link	c.4262G>C	p.Ser1421Thr	missense_variant	Exon 27 of 29	2		ENSP00000426948.1		E9PCH4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727244

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;.;.;.;.

Eigen

Benign

-0.051

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.16

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;.;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.68

N;.;N;.;N

REVEL

Benign

0.089

Sift

Benign

0.080

T;.;T;.;T

Sift4G

Benign

0.22

T;T;T;T;T

Polyphen

0.0090

B;B;.;.;.

Vest4

0.31

MutPred

0.23

.;.;.;.;Gain of catalytic residue at S1421 (P = 0.0112);

MVP

0.48

MPC

0.18, 0.17

ClinPred

0.78

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.20

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over