2-235709180-T-A

Variant names:

• chr2-235709180-T-A
• rs755003432
• NM_001037131.3:c.165T>A

Variant summary

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

The NM_001037131.3(AGAP1):​c.165T>A​(p.Asp55Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AGAP1 NM_001037131.3 missense, splice_region
• Scores: Splicing: ADA: 0.0003867
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.40

Genes affected

AGAP1 (HGNC:16922): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 1) This gene encodes a member of an ADP-ribosylation factor GTPase-activating protein family involved in membrane trafficking and cytoskeleton dynamics. This gene functions as a direct regulator of the adaptor-related protein complex 3 on endosomes. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

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
AGAP1	NM_001037131.3	c.165T>A	p.Asp55Glu	missense_variant, splice_region_variant	Exon 2 of 18	ENST00000304032.13	NP_001032208.1
AGAP1	NM_014914.5	c.165T>A	p.Asp55Glu	missense_variant, splice_region_variant	Exon 2 of 17		NP_055729.2
AGAP1	NM_001244888.2	c.165T>A	p.Asp55Glu	missense_variant, splice_region_variant	Exon 2 of 10		NP_001231817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP1	ENST00000304032.13	c.165T>A	p.Asp55Glu	missense_variant, splice_region_variant	Exon 2 of 18	5	NM_001037131.3	ENSP00000307634.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251472 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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 AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	.;.;T;.;T;T;T;T
Eigen	Benign	0.058
Eigen_PC	Benign	-0.0026
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.88	D;D;D;T;T;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.37	T;T;T;D;T;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.6	L;L;L;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.4	N;N;N;D;N;.;.;.
REVEL	Uncertain	0.40
Sift	Benign	0.24	T;T;T;T;T;.;.;.
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T
Polyphen		1.0, 0.84	.;D;P;.;.;.;.;.
Vest4		0.70
MutPred		0.20		Loss of catalytic residue at D55 (P = 0.1278);Loss of catalytic residue at D55 (P = 0.1278);Loss of catalytic residue at D55 (P = 0.1278);.;.;.;.;.;
MVP		0.79
MPC		0.47
ClinPred		0.75	D
GERP RS		2.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.11
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00039
dbscSNV1_RF	Benign	0.024
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs755003432; hg19: chr2-236617824;