2-130946635-G-A

Position:

• chr2-130946635-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001367493.1(ARHGEF4):​c.3985G>A​(p.Ala1329Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000702 in 1,613,878 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (3 hom.)
• Consequence: ARHGEF4 NM_001367493.1 missense, splice_region
• Scores: Splicing: ADA: 0.9717
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.03

Genes affected

ARHGEF4 (HGNC:684): (Rho guanine nucleotide exchange factor 4) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The protein encoded by this gene may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants encoding different isoforms have been found, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jun 2013]

ARHGEF4 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 2-130946635-G-A is Benign according to our data. Variant chr2-130946635-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3048565.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGEF4	NM_001367493.1	c.3985G>A	p.Ala1329Thr	missense_variant, splice_region_variant	4/14	ENST00000409359.7	NP_001354422.1
ARHGEF4	NM_001375900.1	c.472G>A	p.Ala158Thr	missense_variant, splice_region_variant	3/13		NP_001362829.1
ARHGEF4	NM_015320.4	c.427G>A	p.Ala143Thr	missense_variant, splice_region_variant	5/15		NP_056135.2
ARHGEF4	NM_001375901.1	c.316G>A	p.Ala106Thr	missense_variant, splice_region_variant	6/16		NP_001362830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGEF4	ENST00000409359.7	c.3985G>A	p.Ala1329Thr	missense_variant, splice_region_variant	4/14	5	NM_001367493.1	ENSP00000386794.3

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000374 AC: 94 AN: 251310 Hom.: 0 AF XY: 0.000353 AC XY: 48 AN XY: 135820

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000634

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000739 AC: 1080 AN: 1461590 Hom.: 3 Cov.: 30 AF XY: 0.000729 AC XY: 530 AN XY: 727086

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000927

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74464

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000533 Hom.: 0

Bravo AF: 0.000408

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000654

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ARHGEF4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T;T;.;.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.75	T;T;T;T;T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.048	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L;.;.;.;L
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.16	.;N;.;N;N;N
REVEL	Benign	0.054
Sift	Benign	0.18	.;T;.;D;D;T
Sift4G	Benign	0.63	.;T;T;D;D;T
Polyphen		0.41, 0.55	.;B;.;.;.;P
Vest4		0.19, 0.25, 0.20, 0.24
MVP		0.84
MPC		0.17
ClinPred		0.015	T
GERP RS		3.5
Varity_R		0.055
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.12		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: rs146970275; hg19: chr2-131704208;