Genetic Variant AGAP4:p.Arg612His (chr10-45826141-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001276343.3(AGAP4):c.1835G>A(p.Arg612His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 19)

Exomes 𝑓: 0.000053 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

AGAP4
NM_001276343.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.749

Variant links:

Genes affected

AGAP4 (HGNC:23459): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 4) Predicted to enable GTPase activator activity and metal ion binding activity. Predicted to be involved in regulation of catalytic activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

AGAP4 links:

PARGP1-AGAP4 (HGNC:):

PARGP1-AGAP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08750284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP4	NM_001276343.3 link	c.1835G>A	p.Arg612His	missense_variant	Exon 8 of 8	ENST00000616763.6	NP_001263272.2	Q96P64A0A087X0Z1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP4	ENST00000616763.6 link	c.1835G>A	p.Arg612His	missense_variant	Exon 8 of 8	1	NM_001276343.3	ENSP00000483751.2		A0A087X0Z1
AGAP4	ENST00000448048.7 link	c.1766G>A	p.Arg589His	missense_variant	Exon 7 of 7	1		ENSP00000392513.2		Q96P64

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

138438

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000207

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000315

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000160

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000262

AC:

AN:

38116

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

19332

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000754

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000526

AC:

AN:

1426894

Hom.:

Cov.:

AF XY:

0.0000479

AC XY:

AN XY:

709620

show subpopulations

Gnomad4 AFR exome

AF:

0.000241

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000579

Gnomad4 OTH exome

AF:

0.0000507

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000137

AC:

AN:

138438

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

66674

show subpopulations

Gnomad4 AFR

AF:

0.000207

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000315

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000160

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1766G>A (p.R589H) alteration is located in exon 7 (coding exon 7) of the AGAP4 gene. This alteration results from a G to A substitution at nucleotide position 1766, causing the arginine (R) at amino acid position 589 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.039

T;.;.;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.019

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.0033

MetaRNN

Benign

0.088

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.5

N;.;.;.

REVEL

Benign

0.075

Sift

Benign

0.19

T;.;.;.

Sift4G

Benign

0.30

T;T;T;T

Polyphen

1.0

D;.;.;.

Vest4

0.11

MVP

0.014

ClinPred

0.52

Varity_R

0.079

gMVP

0.062

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over