14-21081734-G-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF40	NM_018071.5	c.2866G>C	p.Val956Leu	missense_variant	Exon 14 of 24	ENST00000298694.9	NP_060541.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF40	ENST00000298694.9	c.2866G>C	p.Val956Leu	missense_variant	Exon 14 of 24	2	NM_018071.5	ENSP00000298694.4

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

GnomAD3 exomes AF: 0.821 AC: 145380 AN: 177164 Hom.: 60366 AF XY: 0.822 AC XY: 79744 AN XY: 96964

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 SAS exome AF: 0.841

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

Gnomad4 AFR exome AF: 0.795

Gnomad4 AMR exome AF: 0.897

Gnomad4 ASJ exome AF: 0.866

Gnomad4 EAS exome AF: 0.507

Gnomad4 SAS exome AF: 0.840

Gnomad4 FIN exome AF: 0.720

Gnomad4 NFE exome AF: 0.863

Gnomad4 OTH exome AF: 0.841

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

Gnomad4 AFR AF: 0.797

Gnomad4 AMR AF: 0.895

Gnomad4 ASJ AF: 0.864

Gnomad4 EAS AF: 0.538

Gnomad4 SAS AF: 0.835

Gnomad4 FIN AF: 0.706

Gnomad4 NFE AF: 0.863

Gnomad4 OTH AF: 0.847

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 v4.3

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
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

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