4-85994903-C-G

Position:

• chr4-85994903-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001025616.3(ARHGAP24):​c.1249C>G​(p.Pro417Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0155 in 1,614,032 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 31)
  • Exomes 𝑓: 0.016 (270 hom.)
• Consequence: ARHGAP24 NM_001025616.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.85

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035718977).
• BP6: Variant 4-85994903-C-G is Benign according to our data. Variant chr4-85994903-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1195227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-85994903-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1822/152150) while in subpopulation NFE AF= 0.016 (1091/68016). AF 95% confidence interval is 0.0152. There are 23 homozygotes in gnomad4. There are 874 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3	c.1249C>G	p.Pro417Ala	missense_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.1249C>G	p.Pro417Ala	missense_variant	9/10	2	NM_001025616.3	ENSP00000378611.1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1822 AN: 152030 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.00312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0760

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.00444

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0128 AC: 3224 AN: 251302 Hom.: 48 AF XY: 0.0129 AC XY: 1753 AN XY: 135800

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00873

Gnomad ASJ exome AF: 0.0714

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00572

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0159 AC: 23201 AN: 1461882 Hom.: 270 Cov.: 33 AF XY: 0.0156 AC XY: 11341 AN XY: 727244

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00888

Gnomad4 ASJ exome AF: 0.0704

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00563

Gnomad4 FIN exome AF: 0.00423

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0168

GnomAD4 genome AF: 0.0120 AC: 1822 AN: 152150 Hom.: 23 Cov.: 31 AF XY: 0.0118 AC XY: 874 AN XY: 74378

Gnomad4 AFR AF: 0.00311

Gnomad4 AMR AF: 0.0149

Gnomad4 ASJ AF: 0.0760

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00541

Gnomad4 FIN AF: 0.00444

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0188 Hom.: 26

Bravo AF: 0.0122

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0192 AC: 165

ExAC AF: 0.0113 AC: 1377

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0193

EpiControl AF: 0.0183

ClinVar

Significance: Benign/Likely 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 30, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2022	See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.034	T;.;T;.
Eigen	Benign	0.037
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.43	B;B;.;B
Vest4		0.075
MPC		0.32
ClinPred		0.020	T
GERP RS		4.7
Varity_R		0.24
gMVP		0.49

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: rs35521695; hg19: chr4-86916056;