chr14-21081734-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 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. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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: 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
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05036375).

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>A	p.Val956Met	missense	Exon 14 of 24	NP_060541.3
	ARHGEF40	NM_001278529.2		c.724G>A	p.Val242Met	missense	Exon 14 of 24	NP_001265458.1
	ARHGEF40	NM_001278530.2		c.724G>A	p.Val242Met	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>A	p.Val956Met	missense	Exon 14 of 24	ENSP00000298694.4
	ARHGEF40	ENST00000553709.5	TSL:1	n.*1030G>A		non_coding_transcript_exon	Exon 14 of 24	ENSP00000452283.1
	ARHGEF40	ENST00000554514.1	TSL:1	n.346G>A		non_coding_transcript_exon	Exon 2 of 10

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD2 exomes AF: 0.0000113 AC: 2 AN: 177164 AF XY: 0.0000103

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32518

American (AMR) AF: 0.00 AC: 0 AN: 38268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25444

East Asian (EAS) AF: 0.00 AC: 0 AN: 37322

South Asian (SAS) AF: 0.00 AC: 0 AN: 82772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092416

Other (OTH) AF: 0.00 AC: 0 AN: 58928

GnomAD4 genome Cov.: 36

ExAC AF: 0.0000178 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.1
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
Mutation Taster		=100/0	polymorphism

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;