19-41884477-C-A

Variant names:

• chr19-41884477-C-A
• rs1555844905
• ENST00000378152.8:c.10C>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.10C>A​(p.Leu4Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. L4F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ARHGEF1 NM_199002.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.136
• 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

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=0.08231565).

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.-20+1188C>A		intron	N/A	NP_004697.2
	ARHGEF1	NM_199002.2		c.10C>A	p.Leu4Ile	missense	Exon 1 of 29	NP_945353.1	Q92888-3
	ARHGEF1	NM_001396000.1		c.-20+1188C>A		intron	N/A	NP_001382929.1	M0QZR4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF1	ENST00000378152.8	TSL:1	c.10C>A	p.Leu4Ile	missense	Exon 1 of 27	ENSP00000367394.3	Q92888-4
	ARHGEF1	ENST00000337665.8	TSL:1	c.10C>A	p.Leu4Ile	missense	Exon 1 of 29	ENSP00000337261.3	Q92888-3
	ARHGEF1	ENST00000354532.8	TSL:1 MANE Select	c.-20+1188C>A		intron	N/A	ENSP00000346532.3	Q92888-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455436 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724332

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.0000211 AC: 1 AN: 47412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Benign	0.97
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.37	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.14
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.044
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.14	B
Vest4		0.24
MutPred		0.18		Gain of sheet (P = 0.0344)
MVP		0.48
MPC		0.47
ClinPred		0.46	T
GERP RS		2.6
PromoterAI		-0.15	Neutral
gMVP		0.047
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: rs1555844905; hg19: chr19-42388544;