8-1857947-TTTTTC-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_014629.4(ARHGEF10):c.38-8_38-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00498 in 1,610,914 control chromosomes in the GnomAD database, including 64 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (57 hom.)
• Consequence: ARHGEF10 NM_014629.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.32

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.

• BP6: Variant 8-1857947-TTTTTC-T is Benign according to our data. Variant chr8-1857947-TTTTTC-T is described in ClinVar as [Benign]. Clinvar id is 708928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1857947-TTTTTC-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00505 (7374/1458830) while in subpopulation SAS AF= 0.0167 (1438/86140). AF 95% confidence interval is 0.016. There are 57 homozygotes in gnomad4_exome. There are 4018 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 647 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10	NM_014629.4	c.38-8_38-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000349830.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.38-8_38-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014629.4	P4
ARHGEF10	ENST00000518288.5	c.110-8_110-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
ARHGEF10	ENST00000520359.5	c.38-8_38-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A2
ARHGEF10	ENST00000398564.5	c.110-8_110-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 647 AN: 151966 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00479

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00599 AC: 1502 AN: 250580 Hom.: 18 AF XY: 0.00671 AC XY: 909 AN XY: 135500

Gnomad AFR exome AF: 0.000743

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000436

Gnomad SAS exome AF: 0.0155

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00533

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.00505 AC: 7374 AN: 1458830 Hom.: 57 AF XY: 0.00553 AC XY: 4018 AN XY: 725974

Gnomad4 AFR exome AF: 0.000628

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.00426

Gnomad4 OTH exome AF: 0.00511

GnomAD4 genome AF: 0.00426 AC: 648 AN: 152084 Hom.: 7 Cov.: 32 AF XY: 0.00452 AC XY: 336 AN XY: 74362

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00478

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.0133

Gnomad4 NFE AF: 0.00472

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00299 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

ARHGEF10-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2019

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200470716; hg19: chr8-1806113;