4-85994529-G-T

Variant summary

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

The NM_001025616.3(ARHGAP24):c.929-54G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,526,454 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0089 (10 hom., cov: 32)
  • Exomes 𝑓: 0.012 (113 hom.)
• Consequence: ARHGAP24 NM_001025616.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.135

Genes affected

ARHGAP24 (HGNC:25361): (Rho GTPase activating protein 24) This gene encodes a Rho-GTPase activating protein, which is specific for the small GTPase family member Rac. Binding of the encoded protein by filamin A targets it to sites of membrane protrusion, where it antognizes Rac. This results in suppression of lamellae formation and promotion of retraction to regulate cell polarity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

MAPK10 (HGNC:6872): (mitogen-activated protein kinase 10) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as integration points for multiple biochemical signals, and thus are involved in a wide variety of cellular processes, such as proliferation, differentiation, transcription regulation and development. This kinase is specifically expressed in a subset of neurons in the nervous system, and is activated by threonine and tyrosine phosphorylation. Targeted deletion of this gene in mice suggests that it may have a role in stress-induced neuronal apoptosis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-85994529-G-T is Benign according to our data. Variant chr4-85994529-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1209507.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP24	NM_001025616.3	c.929-54G>T		intron_variant		ENST00000395184.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP24	ENST00000395184.6	c.929-54G>T		intron_variant		2	NM_001025616.3	P1

Frequencies

GnomAD3 genomes AF: 0.00896 AC: 1362 AN: 152084 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00642

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.00862

GnomAD4 exome AF: 0.0119 AC: 16301 AN: 1374252 Hom.: 113 AF XY: 0.0114 AC XY: 7828 AN XY: 688794

Gnomad4 AFR exome AF: 0.00222

Gnomad4 AMR exome AF: 0.00632

Gnomad4 ASJ exome AF: 0.00668

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.000249

Gnomad4 FIN exome AF: 0.00716

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.00959

GnomAD4 genome AF: 0.00894 AC: 1361 AN: 152202 Hom.: 10 Cov.: 32 AF XY: 0.00832 AC XY: 619 AN XY: 74398

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00642

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.00981 Hom.: 1

Bravo AF: 0.00923

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

GeneDx

Apr 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.42
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs147851787; hg19: chr4-86915682;