rs17683288

Positions:

• chr8-1929314-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014629.4(ARHGEF10):​c.2950T>G​(p.Ser984Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0634 in 1,613,890 control chromosomes in the GnomAD database, including 3,648 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S984S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.050 (265 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3383 hom.)
• Consequence: ARHGEF10 NM_014629.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.48

Genes affected

ARHGEF10 (HGNC:14103): (Rho guanine nucleotide exchange factor 10) This gene encodes a Rho guanine nucleotide exchange factor (GEF). Rho GEFs regulate the activity of small Rho GTPases by stimulating the exchange of guanine diphosphate (GDP) for guanine triphosphate (GTP) and may play a role in neural morphogenesis. Mutations in this gene are associated with slowed nerve conduction velocity (SNCV). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015234053).
• BP6: Variant 8-1929314-T-G is Benign according to our data. Variant chr8-1929314-T-G is described in ClinVar as [Benign]. Clinvar id is 1229340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1929314-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0704 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10	NM_014629.4	c.2950T>G	p.Ser984Ala	missense_variant	25/29	ENST00000349830.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.2950T>G	p.Ser984Ala	missense_variant	25/29	1	NM_014629.4	P4

Frequencies

GnomAD3 genomes AF: 0.0504 AC: 7674 AN: 152202 Hom.: 265 Cov.: 33

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.0812

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0720

Gnomad OTH AF: 0.0554

GnomAD3 exomes AF: 0.0545 AC: 13694 AN: 251466 Hom.: 461 AF XY: 0.0560 AC XY: 7613 AN XY: 135908

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0839

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0444

Gnomad FIN exome AF: 0.0789

Gnomad NFE exome AF: 0.0722

Gnomad OTH exome AF: 0.0613

GnomAD4 exome AF: 0.0647 AC: 94603 AN: 1461570 Hom.: 3383 Cov.: 32 AF XY: 0.0648 AC XY: 47116 AN XY: 727112

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.0301

Gnomad4 ASJ exome AF: 0.0841

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0433

Gnomad4 FIN exome AF: 0.0781

Gnomad4 NFE exome AF: 0.0707

Gnomad4 OTH exome AF: 0.0584

GnomAD4 genome AF: 0.0504 AC: 7676 AN: 152320 Hom.: 265 Cov.: 33 AF XY: 0.0505 AC XY: 3762 AN XY: 74476

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.0443

Gnomad4 ASJ AF: 0.0827

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0414

Gnomad4 FIN AF: 0.0812

Gnomad4 NFE AF: 0.0721

Gnomad4 OTH AF: 0.0548

Alfa AF: 0.0665 Hom.: 774

Bravo AF: 0.0448

TwinsUK AF: 0.0707 AC: 262

ALSPAC AF: 0.0675 AC: 260

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.0710 AC: 611

ExAC AF: 0.0546 AC: 6629

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.0714

EpiControl AF: 0.0704

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.29
DEOGEN2	Benign	0.023	.;.;.;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.85	D
MetaRNN	Benign	0.0015	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	.;.;.;L;.
MutationTaster	Benign	0.95	P;P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.95	N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.64	T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T
Polyphen		0.010	B;B;.;.;.
Vest4		0.13
MPC		0.032
ClinPred		0.0079	T
GERP RS		2.7
Varity_R		0.044
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17683288; hg19: chr8-1877480; COSMIC: COSV50664117; COSMIC: COSV50664117;