4-85994762-C-T

Variant names:

• chr4-85994762-C-T
• rs768626255
• NM_001025616.3:c.1108C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001025616.3(ARHGAP24):​c.1108C>T​(p.Pro370Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ARHGAP24 NM_001025616.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.999

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0819034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGAP24	NM_001025616.3	c.1108C>T	p.Pro370Ser	missense_variant	Exon 9 of 10	ENST00000395184.6	NP_001020787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGAP24	ENST00000395184.6	c.1108C>T	p.Pro370Ser	missense_variant	Exon 9 of 10	2	NM_001025616.3	ENSP00000378611.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152050 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251174 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135720

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461870 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152050 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74238

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000567

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 20, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.082	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.029
Sift	Benign	0.033	D;D;D;D
Sift4G	Benign	0.080	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.11
MVP		0.70
MPC		0.15
ClinPred		0.047	T
GERP RS		4.1
Varity_R		0.088
gMVP		0.25

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: rs768626255; hg19: chr4-86915915;