NM_001276343.3:c.1721A>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K574E) has been classified 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276343.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGAP4	NM_001276343.3	MANE Select	c.1721A>T	p.Lys574Met	missense	Exon 8 of 8	NP_001263272.2	A0A087X0Z1
	AGAP4	NM_133446.4		c.1652A>T	p.Lys551Met	missense	Exon 7 of 7	NP_597703.2	Q96P64
	AGAP4	NM_001393377.1		c.1604A>T	p.Lys535Met	missense	Exon 10 of 10	NP_001380306.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGAP4	ENST00000616763.6	TSL:1 MANE Select	c.1721A>T	p.Lys574Met	missense	Exon 8 of 8	ENSP00000483751.2	A0A087X0Z1
	AGAP4	ENST00000448048.7	TSL:1	c.1652A>T	p.Lys551Met	missense	Exon 7 of 7	ENSP00000392513.2	Q96P64
	AGAP4	ENST00000970389.1		c.1715A>T	p.Lys572Met	missense	Exon 8 of 8	ENSP00000640448.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 85850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1106120

Other (OTH) AF: 0.00 AC: 0 AN: 59902

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00455694), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000246 AC: 1 AN: 40640

American (AMR) AF: 0.00 AC: 0 AN: 14670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3334

East Asian (EAS) AF: 0.00 AC: 0 AN: 4914

South Asian (SAS) AF: 0.00 AC: 0 AN: 4378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65506

Other (OTH) AF: 0.00 AC: 0 AN: 1968

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.19
Sift	Uncertain	0.020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.18
ClinPred		1.0	D
Varity_R		0.45
gMVP		0.079
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs1428646434; hg19: chr10-46321703;