10-45825926-T-C

Variant names:

• chr10-45825926-T-C
• rs1169771928
• NM_001276343.3:c.2050A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001276343.3(AGAP4):​c.2050A>G​(p.Lys684Glu) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0052 (1 hom., cov: 18)
  • Exomes 𝑓: 0.0048 (2784 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGAP4 NM_001276343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033278883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP4	NM_001276343.3	c.2050A>G	p.Lys684Glu	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.2050A>G	p.Lys684Glu	missense_variant	Exon 8 of 8	1	NM_001276343.3	ENSP00000483751.2
AGAP4	ENST00000448048.7	c.1981A>G	p.Lys661Glu	missense_variant	Exon 7 of 7	1		ENSP00000392513.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 525 AN: 100152 Hom.: 1 Cov.: 18 FAILED QC

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00503

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00352

Gnomad EAS AF: 0.00844

Gnomad SAS AF: 0.0173

Gnomad FIN AF: 0.00417

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00495

Gnomad OTH AF: 0.00702

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00481 AC: 5689 AN: 1182162 Hom.: 2784 Cov.: 30 AF XY: 0.00615 AC XY: 3593 AN XY: 583968

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.00401

Gnomad4 ASJ exome AF: 0.00279

Gnomad4 EAS exome AF: 0.00562

Gnomad4 SAS exome AF: 0.0428

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.00291

Gnomad4 OTH exome AF: 0.00440

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00521 AC: 522 AN: 100242 Hom.: 1 Cov.: 18 AF XY: 0.00513 AC XY: 249 AN XY: 48526

Gnomad4 AFR AF: 0.00495

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00352

Gnomad4 EAS AF: 0.00847

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.00417

Gnomad4 NFE AF: 0.00495

Gnomad4 OTH AF: 0.00775

Alfa AF: 0.0235 Hom.: 62

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1981A>G (p.K661E) alteration is located in exon 7 (coding exon 7) of the AGAP4 gene. This alteration results from a A to G substitution at nucleotide position 1981, causing the lysine (K) at amino acid position 661 to be replaced by a glutamic acid (E). 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	0.052
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.2
DANN	Benign	0.15
DEOGEN2	Benign	0.0018	T;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.23	T;T;T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.033	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.68	N;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	2.6	N;.;.
REVEL	Benign	0.13
Sift	Benign	1.0	T;.;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.11
MutPred		0.33		Loss of methylation at K661 (P = 2e-04);.;Loss of methylation at K661 (P = 2e-04);
MVP		0.030
ClinPred		0.14	T
Varity_R		0.065
gMVP		0.030

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: rs1169771928; hg19: chr10-46321374;