NM_018125.4:c.346C>A

Variant names:

• chr1-17602215-C-A
• NM_018125.4:c.346C>A

Variant summary

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

The NM_018125.4(ARHGEF10L):​c.346C>A​(p.Arg116Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ARHGEF10L NM_018125.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018125.4. 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
	ARHGEF10L	NM_018125.4	MANE Select	c.346C>A	p.Arg116Ser	missense	Exon 5 of 29	NP_060595.3
	ARHGEF10L	NM_001011722.2		c.346C>A	p.Arg116Ser	missense	Exon 4 of 27	NP_001011722.2	Q9HCE6-2
	ARHGEF10L	NM_001438939.1		c.346C>A	p.Arg116Ser	missense	Exon 5 of 27	NP_001425868.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF10L	ENST00000361221.8	TSL:1 MANE Select	c.346C>A	p.Arg116Ser	missense	Exon 5 of 29	ENSP00000355060.3	Q9HCE6-1
	ARHGEF10L	ENST00000375415.5	TSL:1	c.346C>A	p.Arg116Ser	missense	Exon 4 of 27	ENSP00000364564.1	Q9HCE6-2
	ARHGEF10L	ENST00000970707.1		c.346C>A	p.Arg116Ser	missense	Exon 5 of 29	ENSP00000640766.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1414948 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 699534

African (AFR) AF: 0.00 AC: 0 AN: 32228

American (AMR) AF: 0.00 AC: 0 AN: 38540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25332

East Asian (EAS) AF: 0.00 AC: 0 AN: 36820

South Asian (SAS) AF: 0.00 AC: 0 AN: 80382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087924

Other (OTH) AF: 0.00 AC: 0 AN: 58552

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.19
Sift	Uncertain	0.013	D
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.58
MutPred		0.29		Gain of phosphorylation at R116 (P = 0.0069)
MVP		0.70
MPC		0.37
ClinPred		0.88	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.33
Mutation Taster		=93/7	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

hg19: chr1-17928710;