4-85994441-T-C

Position:

• chr4-85994441-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001025616.3(ARHGAP24):​c.929-142T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 855,484 control chromosomes in the GnomAD database, including 792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.046 (551 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (241 hom.)
• Consequence: ARHGAP24 NM_001025616.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.166

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-85994441-T-C is Benign according to our data. Variant chr4-85994441-T-C is described in ClinVar as [Benign]. Clinvar id is 1225932.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3	c.929-142T>C		intron_variant		ENST00000395184.6	NP_001020787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP24	ENST00000395184.6	c.929-142T>C		intron_variant		2	NM_001025616.3	ENSP00000378611	P1

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 6994 AN: 152214 Hom.: 551 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0248

GnomAD4 exome AF: 0.00605 AC: 4254 AN: 703152 Hom.: 241 AF XY: 0.00518 AC XY: 1929 AN XY: 372214

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.00987

Gnomad4 ASJ exome AF: 0.0149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000300

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000575

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.0460 AC: 7002 AN: 152332 Hom.: 551 Cov.: 32 AF XY: 0.0448 AC XY: 3338 AN XY: 74498

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0344 Hom.: 43

Bravo AF: 0.0519

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs75349882; hg19: chr4-86915594;