NM_001276343.3:c.1728T>G

Variant names:

• chr10-45826248-A-C
• rs1308290050
• NM_001276343.3:c.1728T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001276343.3(AGAP4):​c.1728T>G​(p.Phe576Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: AGAP4 NM_001276343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP4	NM_001276343.3	c.1728T>G	p.Phe576Leu	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.1728T>G	p.Phe576Leu	missense_variant	Exon 8 of 8	1	NM_001276343.3	ENSP00000483751.2
AGAP4	ENST00000448048.7	c.1659T>G	p.Phe553Leu	missense_variant	Exon 7 of 7	1		ENSP00000392513.2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 4 AN: 145896 Hom.: 0 Cov.: 23 FAILED QC

Gnomad AFR AF: 0.0000987

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000274 AC: 4 AN: 145896 Hom.: 0 Cov.: 23 AF XY: 0.0000141 AC XY: 1 AN XY: 70678

Gnomad4 AFR AF: 0.0000987

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1659T>G (p.F553L) alteration is located in exon 7 (coding exon 7) of the AGAP4 gene. This alteration results from a T to G substitution at nucleotide position 1659, causing the phenylalanine (F) at amino acid position 553 to be replaced by a leucine (L). 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	Pathogenic	0.95
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.29	N
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.0023	T
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.2	D;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.031	D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.66
MVP		0.17
ClinPred		1.0	D
Varity_R		0.58
gMVP		0.040

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: rs1308290050; hg19: chr10-46321696;