4-85994770-G-A

Variant names:

• chr4-85994770-G-A
• rs11547776
• NM_001025616.3:c.1116G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001025616.3(ARHGAP24):​c.1116G>A​(p.Arg372Arg) 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:3
• Conservation: PhyloP100: 0.0780
• Publications: 9 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025616.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP24	NM_001025616.3	MANE Select	c.1116G>A	p.Arg372Arg	synonymous	Exon 9 of 10	NP_001020787.2	Q8N264-1
	ARHGAP24	NM_001287805.2		c.861G>A	p.Arg287Arg	synonymous	Exon 7 of 8	NP_001274734.1
	ARHGAP24	NM_031305.3		c.837G>A	p.Arg279Arg	synonymous	Exon 6 of 7	NP_112595.2	Q8N264-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP24	ENST00000395184.6	TSL:2 MANE Select	c.1116G>A	p.Arg372Arg	synonymous	Exon 9 of 10	ENSP00000378611.1	Q8N264-1
	ARHGAP24	ENST00000264343.4	TSL:1	c.837G>A	p.Arg279Arg	synonymous	Exon 6 of 7	ENSP00000264343.4	Q8N264-2
	ARHGAP24	ENST00000395183.6	TSL:1	c.831G>A	p.Arg277Arg	synonymous	Exon 7 of 8	ENSP00000378610.2	Q8N264-3

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

GnomAD2 exomes AF: 0.257 AC: 64471 AN: 251178 AF XY: 0.260

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 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

African (AFR) AF: 0.133 AC: 4437 AN: 33474

American (AMR) AF: 0.331 AC: 14799 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 5015 AN: 26134

East Asian (EAS) AF: 0.281 AC: 11156 AN: 39700

South Asian (SAS) AF: 0.384 AC: 33147 AN: 86258

European-Finnish (FIN) AF: 0.234 AC: 12477 AN: 53416

Middle Eastern (MID) AF: 0.217 AC: 1253 AN: 5768

European-Non Finnish (NFE) AF: 0.220 AC: 244552 AN: 1111986

Other (OTH) AF: 0.232 AC: 14020 AN: 60394

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

African (AFR) AF: 0.139 AC: 5767 AN: 41472

American (AMR) AF: 0.269 AC: 4112 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 651 AN: 3468

East Asian (EAS) AF: 0.282 AC: 1450 AN: 5138

South Asian (SAS) AF: 0.394 AC: 1897 AN: 4812

European-Finnish (FIN) AF: 0.236 AC: 2491 AN: 10558

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14893 AN: 67960

Other (OTH) AF: 0.198 AC: 418 AN: 2110

Alfa AF: 0.184 Hom.: 2297

Bravo AF: 0.206

Asia WGS AF: 0.350 AC: 1213 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.214

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.7
DANN	Benign	0.57
PhyloP100		0.078
Mutation Taster		=100/0	polymorphism (auto)

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