chr1-17602183-G-A

Position:

• chr1-17602183-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018125.4(ARHGEF10L):​c.314G>A​(p.Arg105Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,581,894 control chromosomes in the GnomAD database, including 16 homozygotes. 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (7 hom.)
• Consequence: ARHGEF10L NM_018125.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.289

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033557713).
• BP6: Variant 1-17602183-G-A is Benign according to our data. Variant chr1-17602183-G-A is described in ClinVar as [Benign]. Clinvar id is 733539.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00609 (928/152300) while in subpopulation AFR AF= 0.0209 (867/41562). AF 95% confidence interval is 0.0197. There are 9 homozygotes in gnomad4. There are 432 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10L	NM_018125.4	c.314G>A	p.Arg105Gln	missense_variant	5/29	ENST00000361221.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10L	ENST00000361221.8	c.314G>A	p.Arg105Gln	missense_variant	5/29	1	NM_018125.4	A1
ARHGEF10L	ENST00000375415.5	c.314G>A	p.Arg105Gln	missense_variant	4/27	1		P4
ARHGEF10L	ENST00000482892.1	n.13G>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152182 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00143 AC: 282 AN: 196916 Hom.: 1 AF XY: 0.00104 AC XY: 110 AN XY: 105536

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.000556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000950

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.000708 AC: 1012 AN: 1429594 Hom.: 7 Cov.: 31 AF XY: 0.000627 AC XY: 444 AN XY: 708114

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.00147

Gnomad4 ASJ exome AF: 0.000589

Gnomad4 EAS exome AF: 0.0000529

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000785

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00609 AC: 928 AN: 152300 Hom.: 9 Cov.: 32 AF XY: 0.00580 AC XY: 432 AN XY: 74464

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00252 Hom.: 4

Bravo AF: 0.00728

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0192 AC: 84

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.00174 AC: 208

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0099	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.83	T;T
MetaRNN	Benign	0.0034	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.018
Sift	Benign	0.27	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0010	B;B
Vest4		0.20
MVP		0.14
MPC		0.059
ClinPred		0.0025	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.19

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

Other links and lift over

dbSNP: rs115180098; hg19: chr1-17928678;