Genetic Variant ARHGEF10L:p.Arg214Ile (chr1-17613089-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018125.4(ARHGEF10L):c.641G>T(p.Arg214Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ARHGEF10L
NM_018125.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.87

Variant links:

Genes affected

ARHGEF10L (HGNC:25540): (Rho guanine nucleotide exchange factor 10 like) This gene belongs to the RhoGEF subfamily of RhoGTPases. Members of this subfamily are activated by specific guanine nucleotide exchange factors (GEFs) and are involved in signal transduction. The encoded protein shows cytosolic distribution. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2016]

ARHGEF10L links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20605776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10L	NM_018125.4 link	c.641G>T	p.Arg214Ile	missense_variant	Exon 8 of 29	ENST00000361221.8	NP_060595.3	Q9HCE6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF10L	ENST00000361221.8 link	c.641G>T	p.Arg214Ile	missense_variant	Exon 8 of 29	1	NM_018125.4	ENSP00000355060.3		Q9HCE6-1
ARHGEF10L	ENST00000375415.5 link	c.610-3005G>T		intron_variant	Intron 6 of 26	1		ENSP00000364564.1		Q9HCE6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251300

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.641G>T (p.R214I) alteration is located in exon 8 (coding exon 7) of the ARHGEF10L gene. This alteration results from a G to T substitution at nucleotide position 641, causing the arginine (R) at amino acid position 214 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.0081

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

Eigen

Benign

0.053

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.022

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.19

Sift

Uncertain

0.015

Sift4G

Uncertain

0.024

Polyphen

0.74

Vest4

0.39

MutPred

0.34

Loss of disorder (P = 0.0106);

MVP

0.49

MPC

0.14

ClinPred

0.92

GERP RS

4.0

Varity_R

0.48

gMVP

0.20

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over