chr14-21081734-G-C

Variant names:

• chr14-21081734-G-C
• rs7143633
• NM_018071.5:c.2866G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018071.5(ARHGEF40):​c.2866G>C​(p.Val956Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 1,574,850 control chromosomes in the GnomAD database, including 564,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.82 (52055 hom., cov: 36)
  • Exomes 𝑓: 0.85 (512034 hom.)
• Consequence: ARHGEF40 NM_018071.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 28 publications found

Genes affected

ARHGEF40 (HGNC:25516): (Rho guanine nucleotide exchange factor 40) This gene encodes a protein similar to guanosine nucleotide exchange factors for Rho GTPases. The encoded protein contains in its C-terminus a GEF domain involved in exchange activity and a pleckstrin homology domain. Alternatively spliced transcripts that encode different proteins have been described. [provided by RefSeq, Mar 2014]

ARHGEF40 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.7269605E-7).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.882 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018071.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF40	NM_018071.5	MANE Select	c.2866G>C	p.Val956Leu	missense	Exon 14 of 24	NP_060541.3
	ARHGEF40	NM_001278529.2		c.724G>C	p.Val242Leu	missense	Exon 14 of 24	NP_001265458.1
	ARHGEF40	NM_001278530.2		c.724G>C	p.Val242Leu	missense	Exon 14 of 23	NP_001265459.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF40	ENST00000298694.9	TSL:2 MANE Select	c.2866G>C	p.Val956Leu	missense	Exon 14 of 24	ENSP00000298694.4
	ARHGEF40	ENST00000553709.5	TSL:1	n.*1030G>C		non_coding_transcript_exon	Exon 14 of 24	ENSP00000452283.1
	ARHGEF40	ENST00000554514.1	TSL:1	n.346G>C		non_coding_transcript_exon	Exon 2 of 10

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125380 AN: 152142 Hom.: 52028 Cov.: 36

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.894

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.850

GnomAD2 exomes AF: 0.821 AC: 145380 AN: 177164 AF XY: 0.822

Gnomad AFR exome AF: 0.791

Gnomad AMR exome AF: 0.895

Gnomad ASJ exome AF: 0.869

Gnomad EAS exome AF: 0.532

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.860

Gnomad OTH exome AF: 0.851

GnomAD4 exome AF: 0.846 AC: 1203298 AN: 1422590 Hom.: 512034 Cov.: 100 AF XY: 0.846 AC XY: 596243 AN XY: 704582

African (AFR) AF: 0.795 AC: 25856 AN: 32514

American (AMR) AF: 0.897 AC: 34303 AN: 38260

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 22023 AN: 25440

East Asian (EAS) AF: 0.507 AC: 18924 AN: 37318

South Asian (SAS) AF: 0.840 AC: 69552 AN: 82758

European-Finnish (FIN) AF: 0.720 AC: 35500 AN: 49282

Middle Eastern (MID) AF: 0.846 AC: 4835 AN: 5718

European-Non Finnish (NFE) AF: 0.863 AC: 942756 AN: 1092376

Other (OTH) AF: 0.841 AC: 49549 AN: 58924

GnomAD4 genome AF: 0.824 AC: 125461 AN: 152260 Hom.: 52055 Cov.: 36 AF XY: 0.815 AC XY: 60685 AN XY: 74438

African (AFR) AF: 0.797 AC: 33095 AN: 41538

American (AMR) AF: 0.895 AC: 13694 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 2999 AN: 3470

East Asian (EAS) AF: 0.538 AC: 2783 AN: 5176

South Asian (SAS) AF: 0.835 AC: 4035 AN: 4830

European-Finnish (FIN) AF: 0.706 AC: 7490 AN: 10606

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.863 AC: 58659 AN: 68010

Other (OTH) AF: 0.847 AC: 1793 AN: 2116

Alfa AF: 0.853 Hom.: 16921

Bravo AF: 0.837

TwinsUK AF: 0.861 AC: 3191

ALSPAC AF: 0.869 AC: 3349

ESP6500AA AF: 0.814 AC: 3448

ESP6500EA AF: 0.867 AC: 7161

ExAC AF: 0.795 AC: 89468

Asia WGS AF: 0.719 AC: 2501 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.22
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	6.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		1.1
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.081
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MutPred		0.23		Loss of MoRF binding (P = 0.1143)
MPC		0.23
ClinPred		0.00082	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7143633; hg19: chr14-21549893; COSMIC: COSV53878591;