19-41884477-C-T

Variant names:

• chr19-41884477-C-T
• rs1555844905
• ENST00000378152.8:c.10C>T

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>T​(p.Leu4Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,455,436 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ARHGEF1 NM_199002.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.08353174).

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>T		intron	N/A	NP_004697.2
	ARHGEF1	NM_199002.2		c.10C>T	p.Leu4Phe	missense	Exon 1 of 29	NP_945353.1	Q92888-3
	ARHGEF1	NM_001396000.1		c.-20+1188C>T		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>T	p.Leu4Phe	missense	Exon 1 of 27	ENSP00000367394.3	Q92888-4
	ARHGEF1	ENST00000337665.8	TSL:1	c.10C>T	p.Leu4Phe	missense	Exon 1 of 29	ENSP00000337261.3	Q92888-3
	ARHGEF1	ENST00000354532.8	TSL:1 MANE Select	c.-20+1188C>T		intron	N/A	ENSP00000346532.3	Q92888-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000206 AC: 5 AN: 242870 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000874

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1455436 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 724332

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

American (AMR) AF: 0.0000671 AC: 3 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: 0.00 AC: 0 AN: 47412

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111894

Other (OTH) AF: 0.0000663 AC: 4 AN: 60292

GnomAD4 genome Cov.: 32

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.00000756

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	0.081
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.14
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.041
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.098
MVP		0.49
MPC		0.48
ClinPred		0.59	D
GERP RS		2.6
PromoterAI		-0.10	Neutral
gMVP		0.070
Mutation Taster		=98/2	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;