Genetic Variant NM_001276343.3:c.1702C>T (chr10-45826274-G-A) – 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.1702C>T(p.Arg568Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 147,588 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00018 ( 0 hom., cov: 23)

Exomes 𝑓: 0.000064 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGAP4
NM_001276343.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20442045).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP4	NM_001276343.3 link	c.1702C>T	p.Arg568Cys	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.1702C>T	p.Arg568Cys	missense_variant	Exon 8 of 8	1	NM_001276343.3	ENSP00000483751.2		A0A087X0Z1
AGAP4	ENST00000448048.7 link	c.1633C>T	p.Arg545Cys	missense_variant	Exon 7 of 7	1		ENSP00000392513.2		Q96P64

Frequencies

GnomAD3 genomes

AF:

0.000176

AC:

AN:

147470

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00102

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000223

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000759

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000638

AC:

AN:

1456650

Hom.:

Cov.:

AF XY:

0.0000621

AC XY:

AN XY:

724636

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000640

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.000176

AC:

AN:

147588

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

AN XY:

71682

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.00102

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000224

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000759

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000253

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1633C>T (p.R545C) alteration is located in exon 7 (coding exon 7) of the AGAP4 gene. This alteration results from a C to T substitution at nucleotide position 1633, causing the arginine (R) at amino acid position 545 to be replaced by a cysteine (C). 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

0.11

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Pathogenic

3.8

H;.;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.0

D;.;.;.

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.30

MVP

0.21

ClinPred

1.0

Varity_R

0.58

gMVP

0.054

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

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