8-1857950-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014629.4(ARHGEF10):c.38-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,594,746 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (37 hom.)
• Consequence: ARHGEF10 NM_014629.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004788
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.213

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-1857950-T-C is Benign according to our data. Variant chr8-1857950-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 439416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1857950-T-C is described in Lovd as [Benign]. Variant chr8-1857950-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 529 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10	NM_014629.4	c.38-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000349830.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.38-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014629.4	P4
ARHGEF10	ENST00000518288.5	c.110-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1
ARHGEF10	ENST00000520359.5	c.38-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1		A2
ARHGEF10	ENST00000398564.5	c.110-10T>C		splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 529 AN: 150836 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000702

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00255

Gnomad FIN AF: 0.000290

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00678

GnomAD3 exomes AF: 0.00389 AC: 976 AN: 250758 Hom.: 7 AF XY: 0.00434 AC XY: 589 AN XY: 135596

Gnomad AFR exome AF: 0.000680

Gnomad AMR exome AF: 0.00536

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00367

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00458 AC: 6615 AN: 1443794 Hom.: 37 Cov.: 32 AF XY: 0.00463 AC XY: 3325 AN XY: 717756

Gnomad4 AFR exome AF: 0.000689

Gnomad4 AMR exome AF: 0.00535

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00377

Gnomad4 FIN exome AF: 0.000230

Gnomad4 NFE exome AF: 0.00480

Gnomad4 OTH exome AF: 0.00489

GnomAD4 genome AF: 0.00350 AC: 529 AN: 150952 Hom.: 1 Cov.: 32 AF XY: 0.00359 AC XY: 265 AN XY: 73776

Gnomad4 AFR AF: 0.000700

Gnomad4 AMR AF: 0.00805

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00255

Gnomad4 FIN AF: 0.000290

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00671

Alfa AF: 0.00397 Hom.: 0

Bravo AF: 0.00417

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant slowed nerve conduction velocity Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 08, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Feb 16, 2016	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	5.1
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0020
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: rs138713415; hg19: chr8-1806116;