4-85994529-G-T

Variant names:

• chr4-85994529-G-T
• rs147851787
• NM_001025616.3:c.929-54G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.135
• 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 -16 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_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1361 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3	c.929-54G>T		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.929-54G>T		intron_variant	Intron 8 of 9	2	NM_001025616.3	ENSP00000378611.1

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

African (AFR) AF: 0.00222 AC: 70 AN: 31570

American (AMR) AF: 0.00632 AC: 282 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00668 AC: 171 AN: 25592

East Asian (EAS) AF: 0.0000510 AC: 2 AN: 39224

South Asian (SAS) AF: 0.000249 AC: 21 AN: 84284

European-Finnish (FIN) AF: 0.00716 AC: 382 AN: 53356

Middle Eastern (MID) AF: 0.00267 AC: 15 AN: 5616

European-Non Finnish (NFE) AF: 0.0143 AC: 14807 AN: 1032552

Other (OTH) AF: 0.00959 AC: 551 AN: 57454

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

African (AFR) AF: 0.00274 AC: 114 AN: 41546

American (AMR) AF: 0.0118 AC: 180 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00642 AC: 68 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0142 AC: 965 AN: 68004

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.0100 Hom.: 2

Bravo AF: 0.00923

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.42
DANN	Benign	0.64
PhyloP100		-0.14
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: rs147851787; hg19: chr4-86915682;