chr10-45826274-G-A

Variant names:

• chr10-45826274-G-A
• rs1482221451
• NM_001276343.3:c.1702C>T

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00

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]

PARGP1-AGAP4 (HGNC:):

ACMG classification

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	c.1702C>T	p.Arg568Cys	missense_variant	Exon 8 of 8	ENST00000616763.6	NP_001263272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP4	ENST00000616763.6	c.1702C>T	p.Arg568Cys	missense_variant	Exon 8 of 8	1	NM_001276343.3	ENSP00000483751.2
AGAP4	ENST00000448048.7	c.1633C>T	p.Arg545Cys	missense_variant	Exon 7 of 7	1		ENSP00000392513.2

Frequencies

GnomAD3 genomes AF: 0.000176 AC: 26 AN: 147470 Hom.: 0 Cov.: 23

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: 93 AN: 1456650 Hom.: 0 Cov.: 30 AF XY: 0.0000621 AC XY: 45 AN XY: 724636

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: 26 AN: 147588 Hom.: 0 Cov.: 23 AF XY: 0.000223 AC XY: 16 AN XY: 71682

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.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.8	H;.;.;.
PrimateAI	Uncertain	0.57	T
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	D
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

Other links and lift over

dbSNP: rs1482221451; hg19: chr10-46321722;