chr10-45826219-G-A

Variant names:

• chr10-45826219-G-A
• rs1554896179
• NM_001276343.3:c.1757C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001276343.3(AGAP4):​c.1757C>T​(p.Ser586Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000068 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGAP4 NM_001276343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.16

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23944807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP4	NM_001276343.3	c.1757C>T	p.Ser586Phe	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.1757C>T	p.Ser586Phe	missense_variant	Exon 8 of 8	1	NM_001276343.3	ENSP00000483751.2
AGAP4	ENST00000448048.7	c.1688C>T	p.Ser563Phe	missense_variant	Exon 7 of 7	1		ENSP00000392513.2

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD3 exomes AF: 0.0000237 AC: 1 AN: 42110 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 21256

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000678 AC: 8 AN: 1179252 Hom.: 0 Cov.: 19 AF XY: 0.00000510 AC XY: 3 AN XY: 588458

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000281

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000786

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1688C>T (p.S563F) 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 1688, causing the serine (S) at amino acid position 563 to be replaced by a phenylalanine (F). 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	0.30
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.6	M;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.0	D;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D;.;.;.
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.13
MVP		0.26
ClinPred		0.44	T
Varity_R		0.20
gMVP		0.042

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: rs1554896179; hg19: chr10-46321667;