NM_001025616.3:c.929-2448A>G

Variant names:

• chr4-85992135-A-G
• rs566576391
• NM_001025616.3:c.929-2448A>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.929-2448A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00099 in 397,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: ARHGAP24 NM_001025616.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.05
• 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=-0.88).
• BP6: Variant 4-85992135-A-G is Benign according to our data. Variant chr4-85992135-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3910402.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3	c.929-2448A>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.929-2448A>G		intron_variant	Intron 8 of 9	2	NM_001025616.3	ENSP00000378611.1

Frequencies

GnomAD3 genomes AF: 0.000625 AC: 95 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00121 AC: 298 AN: 245650 Hom.: 0 Cov.: 0 AF XY: 0.00133 AC XY: 166 AN XY: 124472

African (AFR) AF: 0.000280 AC: 2 AN: 7146

American (AMR) AF: 0.00 AC: 0 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 116 AN: 9216

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 3028

European-Finnish (FIN) AF: 0.000432 AC: 9 AN: 20820

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

European-Non Finnish (NFE) AF: 0.000927 AC: 146 AN: 157500

Other (OTH) AF: 0.00135 AC: 22 AN: 16338

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000686 AC XY: 51 AN XY: 74390

African (AFR) AF: 0.0000241 AC: 1 AN: 41548

American (AMR) AF: 0.000131 AC: 2 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 43 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000801

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.024
DANN	Benign	0.69
FATHMM_MKL	Benign	0.023	N
PhyloP100		-1.0
GERP RS		-3.7
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: rs566576391; hg19: chr4-86913288;