4-85994695-T-C

Position:

• chr4-85994695-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001025616.3(ARHGAP24):​c.1041T>C​(p.Asn347=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,613,714 control chromosomes in the GnomAD database, including 53,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7653 hom., cov: 31)
  • Exomes 𝑓: 0.24 (45746 hom.)
• Consequence: ARHGAP24 NM_001025616.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.493

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-85994695-T-C is Benign according to our data. Variant chr4-85994695-T-C is described in ClinVar as [Benign]. Clinvar id is 1268964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.493 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3	c.1041T>C	p.Asn347=	synonymous_variant	9/10	ENST00000395184.6	NP_001020787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARHGAP24	ENST00000395184.6	c.1041T>C	p.Asn347=	synonymous_variant	9/10	2	NM_001025616.3	ENSP00000378611	P1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45596 AN: 151740 Hom.: 7645 Cov.: 31

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.257

GnomAD3 exomes AF: 0.281 AC: 70570 AN: 251066 Hom.: 10792 AF XY: 0.279 AC XY: 37834 AN XY: 135668

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.286

Gnomad SAS exome AF: 0.384

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.243 AC: 354862 AN: 1461856 Hom.: 45746 Cov.: 36 AF XY: 0.246 AC XY: 178871 AN XY: 727234

Gnomad4 AFR exome AF: 0.453

Gnomad4 AMR exome AF: 0.348

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.281

Gnomad4 SAS exome AF: 0.385

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.221

Gnomad4 OTH exome AF: 0.253

GnomAD4 genome AF: 0.301 AC: 45646 AN: 151858 Hom.: 7653 Cov.: 31 AF XY: 0.306 AC XY: 22670 AN XY: 74192

Gnomad4 AFR AF: 0.454

Gnomad4 AMR AF: 0.300

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.284

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.236

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.256

Alfa AF: 0.251 Hom.: 3864

Bravo AF: 0.308

Asia WGS AF: 0.370 AC: 1285 AN: 3478

EpiCase AF: 0.218

EpiControl AF: 0.215

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.091
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10003909; hg19: chr4-86915848; COSMIC: COSV51987615;