Variant X-136669534-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004840.3(ARHGEF6):c.2138G>A(p.Ser713Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000824 in 1,092,046 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000082 ( 0 hom. 4 hem. )

Consequence

ARHGEF6
NM_004840.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.93

Variant links:

Genes affected

ARHGEF6 (HGNC:685): (Rac/Cdc42 guanine nucleotide exchange factor 6) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein belongs to a family of cytoplasmic proteins that activate the Ras-like family of Rho proteins by exchanging bound GDP for GTP. It may form a complex with G proteins and stimulate Rho-dependent signals. This protein is activated by PI3-kinase. Mutations in this gene can cause X-chromosomal non-specific cognitive disability. [provided by RefSeq, Jul 2008]

ARHGEF6 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF6	NM_004840.3 linkuse as main transcript	c.2138G>A	p.Ser713Asn	missense_variant, splice_region_variant	21/22	ENST00000250617.7	NP_004831.1	Q15052-1Q8N4Q3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ARHGEF6	ENST00000250617.7 linkuse as main transcript	c.2138G>A	p.Ser713Asn	missense_variant, splice_region_variant	21/22	1	NM_004840.3	ENSP00000250617.6	Q15052-1
ARHGEF6	ENST00000370622.5 linkuse as main transcript	c.1676G>A	p.Ser559Asn	missense_variant, splice_region_variant	20/21	1		ENSP00000359656.1	Q15052-2
ARHGEF6	ENST00000370620.5 linkuse as main transcript	c.1676G>A	p.Ser559Asn	missense_variant, splice_region_variant	20/21	2		ENSP00000359654.1	Q15052-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000824

AC:

AN:

1092046

Hom.:

Cov.:

AF XY:

0.0000112

AC XY:

AN XY:

357646

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:

0.00000837

Gnomad4 OTH exome

AF:

0.0000436

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2024

The c.2138G>A (p.S713N) alteration is located in exon 21 (coding exon 21) of the ARHGEF6 gene. This alteration results from a G to A substitution at nucleotide position 2138, causing the serine (S) at amino acid position 713 to be replaced by an asparagine (N). 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

.;.;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Uncertain

0.036

MutationAssessor

Uncertain

2.9

.;.;M

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0060

D;D;D

Sift4G

Benign

0.12

T;T;T

Polyphen

1.0

.;.;D

Vest4

0.84

MutPred

0.22

.;.;Loss of sheet (P = 0.0181);

MVP

0.89

MPC

0.71

ClinPred

0.95

GERP RS

5.7

Varity_R

0.74

gMVP

0.53

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over