rs1555845520

Variant names:

• chr19-41888082-G-C
• rs1555845520
• ENST00000378152.8:c.45G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-41888082-G-C
• chr19-41888082-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199002.2(ARHGEF1):​c.45G>C​(p.Glu15Asp) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E15Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ARHGEF1 NM_199002.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

Genes affected

ARHGEF1 (HGNC:681): (Rho guanine nucleotide exchange factor 1) Rho GTPases play a fundamental role in numerous cellular processes that are initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form complex with G proteins and stimulate Rho-dependent signals. Multiple alternatively spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been defined. [provided by RefSeq, Jul 2008]

ARHGEF1 Gene-Disease associations (from GenCC):

• immunodeficiency 62

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000296972 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12190887).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199002.2. 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
	ARHGEF1	NM_004706.4	MANE Select	c.-1G>C		5_prime_UTR	Exon 2 of 29	NP_004697.2
	ARHGEF1	NM_199002.2		c.45G>C	p.Glu15Asp	missense	Exon 2 of 29	NP_945353.1	Q92888-3
	ARHGEF1	NM_001396000.1		c.-1G>C		5_prime_UTR	Exon 2 of 30	NP_001382929.1	M0QZR4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF1	ENST00000378152.8	TSL:1	c.45G>C	p.Glu15Asp	missense	Exon 2 of 27	ENSP00000367394.3	Q92888-4
	ARHGEF1	ENST00000337665.8	TSL:1	c.45G>C	p.Glu15Asp	missense	Exon 2 of 29	ENSP00000337261.3	Q92888-3
	ARHGEF1	ENST00000354532.8	TSL:1 MANE Select	c.-1G>C		5_prime_UTR	Exon 2 of 29	ENSP00000346532.3	Q92888-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.14
Sift	Benign	0.16	T
Sift4G	Benign	0.62	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.077		Gain of loop (P = 0.024)
MVP		0.60
MPC		0.41
ClinPred		0.27	T
GERP RS		0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.096
Mutation Taster		=97/3	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: rs1555845520; hg19: chr19-42392153;