Genetic Variant ARHGEF10L:p.Phe101Leu (chr1-17602172-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018125.4(ARHGEF10L):c.303C>A(p.Phe101Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 7.0e-7 ( 0 hom. )

Consequence

ARHGEF10L
NM_018125.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.758

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035342872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF10L	NM_018125.4 link	c.303C>A	p.Phe101Leu	missense_variant	Exon 5 of 29	ENST00000361221.8	NP_060595.3	Q9HCE6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ARHGEF10L	ENST00000361221.8 link	c.303C>A	p.Phe101Leu	missense_variant	Exon 5 of 29	1	NM_018125.4	ENSP00000355060.3	Q9HCE6-1
ARHGEF10L	ENST00000375415.5 link	c.303C>A	p.Phe101Leu	missense_variant	Exon 4 of 27	1		ENSP00000364564.1	Q9HCE6-2
ARHGEF10L	ENST00000482892.1 link	n.2C>A		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1430958

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

708936

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:

9.12e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000611

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.303C>A (p.F101L) alteration is located in exon 5 (coding exon 4) of the ARHGEF10L gene. This alteration results from a C to A substitution at nucleotide position 303, causing the phenylalanine (F) at amino acid position 101 to be replaced by a leucine (L). 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

Benign

0.31

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.41

DEOGEN2

Benign

0.018

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.49

T;T

M_CAP

Benign

0.0085

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.51

N;N

REVEL

Benign

0.068

Sift

Benign

0.28

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.0

B;B

Vest4

0.14

MutPred

0.22

Gain of MoRF binding (P = 0.1255);Gain of MoRF binding (P = 0.1255);

MVP

0.061

MPC

0.059

ClinPred

0.11

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.085

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over