NM_018071.5:c.877A>G

Variant names:

• chr14-21074607-A-G
• rs12889267
• NM_018071.5:c.877A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018071.5(ARHGEF40):​c.877A>G​(p.Lys293Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,567,194 control chromosomes in the GnomAD database, including 21,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1836 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19837 hom.)
• Consequence: ARHGEF40 NM_018071.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004220277).
• BP6: Variant 14-21074607-A-G is Benign according to our data. Variant chr14-21074607-A-G is described in ClinVar as Benign. ClinVar VariationId is 1298043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.271 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF40	NM_018071.5	MANE Select	c.877A>G	p.Lys293Glu	missense	Exon 3 of 24	NP_060541.3
	ARHGEF40	NM_001278529.2		c.-1293A>G		5_prime_UTR	Exon 3 of 24	NP_001265458.1	Q8TER5-2
	ARHGEF40	NM_001278530.2		c.-1099A>G		5_prime_UTR	Exon 3 of 23	NP_001265459.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF40	ENST00000298694.9	TSL:2 MANE Select	c.877A>G	p.Lys293Glu	missense	Exon 3 of 24	ENSP00000298694.4	Q8TER5-1
	ARHGEF40	ENST00000555038.5	TSL:1	c.877A>G	p.Lys293Glu	missense	Exon 3 of 4	ENSP00000451335.1	G3V3N2
	ARHGEF40	ENST00000553709.5	TSL:1	n.877A>G		non_coding_transcript_exon	Exon 3 of 24	ENSP00000452283.1	G3V5C1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19463 AN: 151942 Hom.: 1837 Cov.: 32

Gnomad AFR AF: 0.0318

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0281

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.164 AC: 29680 AN: 181004 AF XY: 0.161

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0283

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.158

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.159 AC: 225662 AN: 1415136 Hom.: 19837 Cov.: 37 AF XY: 0.159 AC XY: 111609 AN XY: 699800

African (AFR) AF: 0.0243 AC: 794 AN: 32650

American (AMR) AF: 0.346 AC: 12554 AN: 36308

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2692 AN: 24706

East Asian (EAS) AF: 0.0303 AC: 1165 AN: 38412

South Asian (SAS) AF: 0.168 AC: 13646 AN: 81008

European-Finnish (FIN) AF: 0.120 AC: 5899 AN: 49026

Middle Eastern (MID) AF: 0.0758 AC: 413 AN: 5446

European-Non Finnish (NFE) AF: 0.166 AC: 180412 AN: 1089058

Other (OTH) AF: 0.138 AC: 8087 AN: 58522

GnomAD4 genome AF: 0.128 AC: 19460 AN: 152058 Hom.: 1836 Cov.: 32 AF XY: 0.129 AC XY: 9580 AN XY: 74338

African (AFR) AF: 0.0317 AC: 1317 AN: 41506

American (AMR) AF: 0.278 AC: 4245 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3468

East Asian (EAS) AF: 0.0283 AC: 146 AN: 5152

South Asian (SAS) AF: 0.170 AC: 814 AN: 4802

European-Finnish (FIN) AF: 0.113 AC: 1196 AN: 10596

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.163 AC: 11048 AN: 67932

Other (OTH) AF: 0.113 AC: 239 AN: 2110

Alfa AF: 0.142 Hom.: 927

Bravo AF: 0.133

TwinsUK AF: 0.169 AC: 628

ALSPAC AF: 0.177 AC: 683

ESP6500AA AF: 0.0332 AC: 145

ESP6500EA AF: 0.146 AC: 1243

ExAC AF: 0.128 AC: 15097

Asia WGS AF: 0.100 AC: 351 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.0067
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.021	D
Polyphen		0.65	P
Vest4		0.13
MPC		0.37
ClinPred		0.035	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.54
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: rs12889267; hg19: chr14-21542766; COSMIC: COSV53880354; COSMIC: COSV53880354;