4-85992138-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001025616.3(ARHGAP24):​c.929-2445T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 397,830 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.016 (34 hom., cov: 32)
  • Exomes 𝑓: 0.021 (86 hom.)
• Consequence: ARHGAP24 NM_001025616.3 intron
• Clinical Significance: Not reported in ClinVar
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004033655).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0162 (2472/152178) while in subpopulation NFE AF = 0.0248 (1689/67998). AF 95% confidence interval is 0.0239. There are 34 homozygotes in GnomAd4. There are 1113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2472 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2472 AN: 152060 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00548

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00886

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.0210 AC: 5169 AN: 245652 Hom.: 86 Cov.: 0 AF XY: 0.0217 AC XY: 2699 AN XY: 124484

African (AFR) AF: 0.00629 AC: 45 AN: 7152

American (AMR) AF: 0.0136 AC: 101 AN: 7432

Ashkenazi Jewish (ASJ) AF: 0.0361 AC: 333 AN: 9214

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

South Asian (SAS) AF: 0.000991 AC: 3 AN: 3028

European-Finnish (FIN) AF: 0.00922 AC: 192 AN: 20820

Middle Eastern (MID) AF: 0.0140 AC: 18 AN: 1290

European-Non Finnish (NFE) AF: 0.0260 AC: 4099 AN: 157500

Other (OTH) AF: 0.0231 AC: 378 AN: 16336

GnomAD4 genome AF: 0.0162 AC: 2472 AN: 152178 Hom.: 34 Cov.: 32 AF XY: 0.0150 AC XY: 1113 AN XY: 74396

African (AFR) AF: 0.00546 AC: 227 AN: 41542

American (AMR) AF: 0.0177 AC: 270 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

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

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00886 AC: 94 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0248 AC: 1689 AN: 67998

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.0159 Hom.: 10

Bravo AF: 0.0171

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0267 AC: 103

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.3
DANN	Benign	0.82
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0040	T;T
PhyloP100		0.038
GERP RS		4.5
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;