Genetic Variant NM_001164431.3:c.599C>G (chr20-38628967-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164431.3(ARHGAP40):c.599C>G(p.Ala200Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000174 in 1,152,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A200D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

ARHGAP40
NM_001164431.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.165

Publications

0 publications found

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]

ARHGAP40 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06121546).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164431.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP40	NM_001164431.3	MANE Select	c.599C>G	p.Ala200Gly	missense	Exon 4 of 15	NP_001157903.2	Q5TG30

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARHGAP40	ENST00000373345.9	TSL:5 MANE Select	c.599C>G	p.Ala200Gly	missense	Exon 4 of 15	ENSP00000362442.5	Q5TG30
ARHGAP40	ENST00000243967.8	TSL:5	c.260C>G	p.Ala87Gly	missense	Exon 2 of 14	ENSP00000243967.4	H7BXE0
ARHGAP40	ENST00000906550.1		c.558+1752C>G		intron	N/A	ENSP00000576609.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000174

AC:

AN:

1152690

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

565204

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24366

American (AMR)

AF:

0.00

AC:

AN:

28216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15924

East Asian (EAS)

AF:

0.00

AC:

AN:

12816

South Asian (SAS)

AF:

0.0000131

AC:

AN:

76162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4400

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

920746

Other (OTH)

AF:

0.0000240

AC:

AN:

41612

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

3.5

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.0078

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.37

M_CAP

Benign

0.023

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

PhyloP100

0.17

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

REVEL

Benign

0.053

Sift

Benign

0.38

Sift4G

Benign

0.52

Vest4

0.060

MutPred

0.083

Loss of loop (P = 0.1242)

MVP

0.040

ClinPred

0.049

GERP RS

-0.59

Varity_R

0.072

gMVP

0.20

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over