chr2-235494840-G-T

Variant names:

• chr2-235494840-G-T
• rs1255540343
• NM_001037131.3:c.154G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001037131.3(AGAP1):​c.154G>T​(p.Ala52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A52A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: AGAP1 NM_001037131.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.86
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11369529).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037131.3. 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
	AGAP1	NM_001037131.3	MANE Select	c.154G>T	p.Ala52Ser	missense	Exon 1 of 18	NP_001032208.1	Q9UPQ3-1
	AGAP1	NM_014914.5		c.154G>T	p.Ala52Ser	missense	Exon 1 of 17	NP_055729.2	Q9UPQ3-2
	AGAP1	NM_001244888.2		c.154G>T	p.Ala52Ser	missense	Exon 1 of 10	NP_001231817.1	Q9UPQ3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGAP1	ENST00000304032.13	TSL:5 MANE Select	c.154G>T	p.Ala52Ser	missense	Exon 1 of 18	ENSP00000307634.7	Q9UPQ3-1
	AGAP1	ENST00000336665.9	TSL:1	c.154G>T	p.Ala52Ser	missense	Exon 1 of 17	ENSP00000338378.5	Q9UPQ3-2
	AGAP1	ENST00000409457.5	TSL:1	c.154G>T	p.Ala52Ser	missense	Exon 1 of 10	ENSP00000387174.1	Q9UPQ3-3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00 AC: 0 AN: 216422 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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 AF: 7.05e-7 AC: 1 AN: 1418086 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 705456

African (AFR) AF: 0.00 AC: 0 AN: 29572

American (AMR) AF: 0.00 AC: 0 AN: 40154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24626

East Asian (EAS) AF: 0.00 AC: 0 AN: 34514

South Asian (SAS) AF: 0.00 AC: 0 AN: 82734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090044

Other (OTH) AF: 0.00 AC: 0 AN: 58264

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.9
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.15
Sift	Benign	0.57	T
Sift4G	Benign	0.89	T
Polyphen		0.0010	B
Vest4		0.055
MutPred		0.23		Gain of phosphorylation at A52 (P = 0.1617)
MVP		0.48
MPC		0.38
ClinPred		0.40	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.28
Mutation Taster		=86/14	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: rs1255540343; hg19: chr2-236403484;