rs548415567

Variant names:

• chr1-17602182-C-T
• rs548415567
• NM_018125.4:c.313C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018125.4(ARHGEF10L):​c.313C>T​(p.Arg105Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,582,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: ARHGEF10L NM_018125.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07542053).

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.313C>T	p.Arg105Trp	missense	Exon 5 of 29	NP_060595.3
	ARHGEF10L	NM_001011722.2		c.313C>T	p.Arg105Trp	missense	Exon 4 of 27	NP_001011722.2	Q9HCE6-2
	ARHGEF10L	NM_001438939.1		c.313C>T	p.Arg105Trp	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.313C>T	p.Arg105Trp	missense	Exon 5 of 29	ENSP00000355060.3	Q9HCE6-1
	ARHGEF10L	ENST00000375415.5	TSL:1	c.313C>T	p.Arg105Trp	missense	Exon 4 of 27	ENSP00000364564.1	Q9HCE6-2
	ARHGEF10L	ENST00000970707.1		c.313C>T	p.Arg105Trp	missense	Exon 5 of 29	ENSP00000640766.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000558 AC: 11 AN: 197276 AF XY: 0.0000756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000334

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000427 AC: 61 AN: 1429732 Hom.: 0 Cov.: 31 AF XY: 0.0000593 AC XY: 42 AN XY: 708232

African (AFR) AF: 0.00 AC: 0 AN: 32686

American (AMR) AF: 0.0000245 AC: 1 AN: 40876

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25484

East Asian (EAS) AF: 0.000132 AC: 5 AN: 37818

South Asian (SAS) AF: 0.000551 AC: 45 AN: 81666

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50340

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1096030

Other (OTH) AF: 0.0000169 AC: 1 AN: 59104

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74466

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000394 Hom.: 0

ExAC AF: 0.0000751 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	Benign	0.079
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.9
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.017	D
Polyphen		0.97	D
Vest4		0.26
MutPred		0.30		Loss of disorder (P = 0.0124)
MVP		0.44
MPC		0.20
ClinPred		0.20	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.26
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs548415567; hg19: chr1-17928677;