NM_001025616.3:c.929-2445T>G

Variant names:

• chr4-85992138-T-G
• rs114573209
• NM_001025616.3:c.929-2445T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001025616.3(ARHGAP24):​c.929-2445T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 397,840 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (3 hom.)
• Consequence: ARHGAP24 NM_001025616.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0380
• Publications: 0 publications found

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]

MAPK10 Gene-Disease associations (from GenCC):

• Lennox-Gastaut syndrome

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-85992138-T-G is Benign according to our data. Variant chr4-85992138-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3778138.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 456 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3	c.929-2445T>G		intron_variant	Intron 8 of 9	ENST00000395184.6	NP_001020787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP24	ENST00000395184.6	c.929-2445T>G		intron_variant	Intron 8 of 9	2	NM_001025616.3	ENSP00000378611.1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 456 AN: 152064 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00390 AC: 957 AN: 245658 Hom.: 3 Cov.: 0 AF XY: 0.00382 AC XY: 475 AN XY: 124486

African (AFR) AF: 0.00140 AC: 10 AN: 7152

American (AMR) AF: 0.00175 AC: 13 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.00966 AC: 89 AN: 9214

East Asian (EAS) AF: 0.00 AC: 0 AN: 22880

South Asian (SAS) AF: 0.00198 AC: 6 AN: 3028

European-Finnish (FIN) AF: 0.00173 AC: 36 AN: 20820

Middle Eastern (MID) AF: 0.00233 AC: 3 AN: 1290

European-Non Finnish (NFE) AF: 0.00461 AC: 726 AN: 157506

Other (OTH) AF: 0.00453 AC: 74 AN: 16336

GnomAD4 genome AF: 0.00300 AC: 456 AN: 152182 Hom.: 2 Cov.: 32 AF XY: 0.00288 AC XY: 214 AN XY: 74398

African (AFR) AF: 0.000891 AC: 37 AN: 41544

American (AMR) AF: 0.00236 AC: 36 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00481 AC: 327 AN: 68000

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.0000458 Hom.: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MAPK10: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.3
DANN	Benign	0.75
PhyloP100		0.038
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114573209; hg19: chr4-86913291;