20-38628967-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164431.3(ARHGAP40):​c.599C>A​(p.Ala200Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,304,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ARHGAP40
NM_001164431.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.165
Variant links:
Genes affected
ARHGAP40 (HGNC:16226): (Rho GTPase activating protein 40) Predicted to enable GTPase activator activity. Predicted to be involved in regulation of actin filament polymerization and regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0088965595).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ARHGAP40NM_001164431.3 linkc.599C>A p.Ala200Asp missense_variant Exon 4 of 15 NP_001157903.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ARHGAP40ENST00000373345.9 linkc.599C>A p.Ala200Asp missense_variant Exon 4 of 15 5 ENSP00000362442.5 Q5TG30
ARHGAP40ENST00000243967.8 linkc.260C>A p.Ala87Asp missense_variant Exon 2 of 14 5 ENSP00000243967.4 H7BXE0

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
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:
0.00000641
AC:
1
AN:
156022
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
82720
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000407
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:
0.0000165
AC:
19
AN:
1152690
Hom.:
0
Cov.:
31
AF XY:
0.0000159
AC XY:
9
AN XY:
565204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000185
Gnomad4 OTH exome
AF:
0.0000481
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000719
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:
0.000110
ExAC
AF:
0.0000391
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 03, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.596C>A (p.A199D) alteration is located in exon 4 (coding exon 4) of the ARHGAP40 gene. This alteration results from a C to A substitution at nucleotide position 596, causing the alanine (A) at amino acid position 199 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
3.6
DANN
Benign
0.67
DEOGEN2
Benign
0.0036
T
Eigen
Benign
-0.94
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.017
N
LIST_S2
Benign
0.35
T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.0089
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
0.34
N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.73
N
REVEL
Benign
0.027
Sift
Benign
0.63
T
Sift4G
Benign
0.60
T
Vest4
0.14
MutPred
0.17
Gain of solvent accessibility (P = 0.0596);
MVP
0.12
ClinPred
0.029
T
GERP RS
-0.59
Varity_R
0.17
gMVP
0.28

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs560382894; hg19: chr20-37257610; API