8-1929314-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 16/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.48

Publications

25 publications found

Variant links:

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]

ARHGEF10 Gene-Disease associations (from GenCC):

autosomal dominant slowed nerve conduction velocity
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
hereditary peripheral neuropathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
peripheral neuropathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ARHGEF10 links:

KBTBD11-OT1 (HGNC:):

KBTBD11-OT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 1229340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
ARHGEF10	NM_014629.4 link	c.2950T>G	p.Ser984Ala	missense_variant	Exon 25 of 29	ENST00000349830.8	NP_055444.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ARHGEF10	ENST00000349830.8 link	c.2950T>G	p.Ser984Ala	missense_variant	Exon 25 of 29	1	NM_014629.4	ENSP00000340297.3
KBTBD11-OT1	ENST00000635855.1 link	n.*2904T>G		non_coding_transcript_exon_variant	Exon 26 of 30	5		ENSP00000489726.1
KBTBD11-OT1	ENST00000635855.1 link	n.*2904T>G		3_prime_UTR_variant	Exon 26 of 30	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes

AF:

0.0504

AC:

7674

AN:

152202

Hom.:

265

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0545

AC:

13694

AN:

251466

AF XY:

0.0560

show subpopulations

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 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.:

AF XY:

0.0648

AC XY:

47116

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0124

AC:

416

AN:

33474

American (AMR)

AF:

0.0301

AC:

1344

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0841

AC:

2198

AN:

26136

East Asian (EAS)

AF:

0.000403

AC:

AN:

39700

South Asian (SAS)

AF:

0.0433

AC:

3736

AN:

86242

European-Finnish (FIN)

AF:

0.0781

AC:

4170

AN:

53420

Middle Eastern (MID)

AF:

0.0945

AC:

537

AN:

5680

European-Non Finnish (NFE)

AF:

0.0707

AC:

78660

AN:

1111814

Other (OTH)

AF:

0.0584

AC:

3526

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

4612

9224

13835

18447

23059

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2752

5504

8256

11008

13760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0504

AC:

7676

AN:

152320

Hom.:

265

Cov.:

AF XY:

0.0505

AC XY:

3762

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0132

AC:

547

AN:

41576

American (AMR)

AF:

0.0443

AC:

678

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0827

AC:

287

AN:

3470

East Asian (EAS)

AF:

0.00116

AC:

AN:

5180

South Asian (SAS)

AF:

0.0414

AC:

200

AN:

4830

European-Finnish (FIN)

AF:

0.0812

AC:

861

AN:

10608

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0721

AC:

4902

AN:

68024

Other (OTH)

AF:

0.0548

AC:

116

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

388

775

1163

1550

1938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0636

Hom.:

974

Bravo

AF:

0.0448

TwinsUK

AF:

0.0707

AC:

262

ALSPAC

AF:

0.0675

AC:

260

ESP6500AA

AF:

0.0150

AC:

ESP6500EA

AF:

0.0710

AC:

611

ExAC

AF:

0.0546

AC:

6629

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0714

EpiControl

AF:

0.0704

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

ARHGEF10-related disorder

Benign:1

May 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.0

.;.;.;T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.0

.;.;.;.;.

MetaRNN

Benign

0.0015

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

.;.;.;L;.

PhyloP100

3.5

PrimateAI

Benign

0.37

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

Vest4

0.13

ClinPred

0.0079

GERP RS

2.7

Varity_R

0.044

gMVP

0.13

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over