4-85994770-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001025616.3(ARHGAP24):c.1116G>A(p.Arg372=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,854 control chromosomes in the GnomAD database, including 45,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3611 hom., cov: 31)
  • Exomes 𝑓: 0.23 (41787 hom.)
• Consequence: ARHGAP24 NM_001025616.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0780

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-85994770-G-A is Benign according to our data. Variant chr4-85994770-G-A is described in ClinVar as [Benign]. Clinvar id is 1274074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.078 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGAP24	NM_001025616.3	c.1116G>A	p.Arg372=	synonymous_variant	9/10	ENST00000395184.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGAP24	ENST00000395184.6	c.1116G>A	p.Arg372=	synonymous_variant	9/10	2	NM_001025616.3	P1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31854 AN: 151886 Hom.: 3618 Cov.: 31

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.257 AC: 64471 AN: 251178 Hom.: 9037 AF XY: 0.260 AC XY: 35343 AN XY: 135720

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.286

Gnomad SAS exome AF: 0.383

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.233 AC: 340856 AN: 1461850 Hom.: 41787 Cov.: 36 AF XY: 0.238 AC XY: 172769 AN XY: 727234

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.281

Gnomad4 SAS exome AF: 0.384

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.210 AC: 31863 AN: 152004 Hom.: 3611 Cov.: 31 AF XY: 0.217 AC XY: 16125 AN XY: 74276

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.282

Gnomad4 SAS AF: 0.394

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.198

Alfa AF: 0.210 Hom.: 1774

Bravo AF: 0.206

Asia WGS AF: 0.350 AC: 1213 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.214

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	5.7
Dann	Benign	0.57

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: rs11547776; hg19: chr4-86915923; COSMIC: COSV51987638;