chr10-45826273-C-T

Variant names:

• chr10-45826273-C-T
• rs1484096310
• NM_001276343.3:c.1703G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001276343.3(AGAP4):​c.1703G>A​(p.Arg568His) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R568P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0055 (2 hom., cov: 23)
  • Exomes 𝑓: 0.00066 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGAP4 NM_001276343.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007595688).

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.1703G>A	p.Arg568His	missense	Exon 8 of 8	NP_001263272.2	A0A087X0Z1
	AGAP4	NM_133446.4		c.1634G>A	p.Arg545His	missense	Exon 7 of 7	NP_597703.2	Q96P64
	AGAP4	NM_001393377.1		c.1586G>A	p.Arg529His	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.1703G>A	p.Arg568His	missense	Exon 8 of 8	ENSP00000483751.2	A0A087X0Z1
	AGAP4	ENST00000448048.7	TSL:1	c.1634G>A	p.Arg545His	missense	Exon 7 of 7	ENSP00000392513.2	Q96P64
	AGAP4	ENST00000970389.1		c.1697G>A	p.Arg566His	missense	Exon 8 of 8	ENSP00000640448.1

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 815 AN: 147416 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00129

Gnomad ASJ AF: 0.000298

Gnomad EAS AF: 0.000405

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000759

Gnomad OTH AF: 0.00400

GnomAD2 exomes AF: 0.00168 AC: 72 AN: 42942 AF XY: 0.000984

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.000734

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.000655 AC: 954 AN: 1456486 Hom.: 8 Cov.: 30 AF XY: 0.000582 AC XY: 422 AN XY: 724542

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

African (AFR) AF: 0.0195 AC: 651 AN: 33374

American (AMR) AF: 0.00128 AC: 57 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000539 AC: 14 AN: 25956

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39678

South Asian (SAS) AF: 0.000233 AC: 20 AN: 85980

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53102

Middle Eastern (MID) AF: 0.000693 AC: 3 AN: 4332

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1109292

Other (OTH) AF: 0.00128 AC: 77 AN: 60076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00552 AC: 814 AN: 147530 Hom.: 2 Cov.: 23 AF XY: 0.00533 AC XY: 382 AN XY: 71686

African (AFR) AF: 0.0191 AC: 779 AN: 40848

American (AMR) AF: 0.00128 AC: 19 AN: 14800

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3352

East Asian (EAS) AF: 0.000406 AC: 2 AN: 4932

South Asian (SAS) AF: 0.00 AC: 0 AN: 4480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000759 AC: 5 AN: 65880

Other (OTH) AF: 0.00396 AC: 8 AN: 2022

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.9
DANN	Benign	0.72
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.17
Sift	Benign	0.21	T
Sift4G	Benign	0.085	T
Polyphen		0.015	B
Vest4		0.17
MVP		0.040
ClinPred		0.080	T
Varity_R		0.16
gMVP		0.044
Mutation Taster		=99/1	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: rs1484096310; hg19: chr10-46321721;