8-1857951-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014629.4(ARHGEF10):c.38-9T>A 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 0.000372 in 1,594,906 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: ARHGEF10 NM_014629.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006174
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-1857951-T-A is Benign according to our data. Variant chr8-1857951-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 782030.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF10	NM_014629.4	c.38-9T>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000349830.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF10	ENST00000349830.8	c.38-9T>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_014629.4	P4
ARHGEF10	ENST00000518288.5	c.110-9T>A		splice_polypyrimidine_tract_variant, intron_variant		1
ARHGEF10	ENST00000520359.5	c.38-9T>A		splice_polypyrimidine_tract_variant, intron_variant		1		A2
ARHGEF10	ENST00000398564.5	c.110-9T>A		splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.000365 AC: 55 AN: 150830 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000237

Gnomad OTH AF: 0.00290

GnomAD3 exomes AF: 0.000283 AC: 71 AN: 250784 Hom.: 1 AF XY: 0.000369 AC XY: 50 AN XY: 135618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000373 AC: 538 AN: 1443960 Hom.: 1 Cov.: 32 AF XY: 0.000361 AC XY: 259 AN XY: 717822

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000877

Gnomad4 ASJ exome AF: 0.000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000721

Gnomad4 FIN exome AF: 0.0000384

Gnomad4 NFE exome AF: 0.000375

Gnomad4 OTH exome AF: 0.000603

GnomAD4 genome AF: 0.000364 AC: 55 AN: 150946 Hom.: 0 Cov.: 32 AF XY: 0.000298 AC XY: 22 AN XY: 73768

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00145

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000237

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000623

EpiCase AF: 0.000273

EpiControl AF: 0.000238

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	7.5
Dann	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.092
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: rs201522949; hg19: chr8-1806117;