chr10-45826255-T-A

Variant names:

• chr10-45826255-T-A
• rs1428646434
• NM_001276343.3:c.1721A>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001276343.3(AGAP4):​c.1721A>T​(p.Lys574Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 146,510 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 0.0000068 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0000034 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGAP4 NM_001276343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26533946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP4	NM_001276343.3	c.1721A>T	p.Lys574Met	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.1721A>T	p.Lys574Met	missense_variant	Exon 8 of 8	1	NM_001276343.3	ENSP00000483751.2
AGAP4	ENST00000448048.7	c.1652A>T	p.Lys551Met	missense_variant	Exon 7 of 7	1		ENSP00000392513.2

Frequencies

GnomAD3 genomes AF: 0.00000683 AC: 1 AN: 146510 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000246

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000344 AC: 5 AN: 1452320 Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3 AN XY: 722532

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000452

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000683 AC: 1 AN: 146510 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 70996

Gnomad4 AFR AF: 0.0000246

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1652A>T (p.K551M) alteration is located in exon 7 (coding exon 7) of the AGAP4 gene. This alteration results from a A to T substitution at nucleotide position 1652, causing the lysine (K) at amino acid position 551 to be replaced by a methionine (M). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T;.;.;.
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.2	D;.;.;.
REVEL	Benign	0.19
Sift	Uncertain	0.020	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.27
MVP		0.18
ClinPred		1.0	D
Varity_R		0.45
gMVP		0.079

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: rs1428646434; hg19: chr10-46321703;