rs7143633

chr14-21081734-G-Achr14-21081734-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018071.5(ARHGEF40):c.2866G>A(p.Val956Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V956L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05036375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF40	NM_018071.5	c.2866G>A	p.Val956Met	missense_variant	14/24	ENST00000298694.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF40	ENST00000298694.9	c.2866G>A	p.Val956Met	missense_variant	14/24	2	NM_018071.5	P1

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD3 exomes AF: 0.0000113 AC: 2 AN: 177164 Hom.: 0 AF XY: 0.0000103 AC XY: 1 AN XY: 96964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000151

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1422718 Hom.: 0 Cov.: 100 AF XY: 0.00 AC XY: 0 AN XY: 704660

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: 0.00

GnomAD4 genome Cov.: 36

ExAC AF: 0.0000178 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.064
Sift	Benign	0.078	T
Sift4G	Uncertain	0.023	D
Polyphen		0.0090	B
Vest4		0.18
MutPred		0.21		Gain of helix (P = 0.132);
MVP		0.19
MPC		0.24
ClinPred		0.11	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.050
gMVP		0.37

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;