chr2-235494853-A-T

Variant names:

• chr2-235494853-A-T
• rs200114461
• NM_001037131.3:c.163+4A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001037131.3(AGAP1):​c.163+4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000474 in 1,562,286 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000050 (1 hom.)
• Consequence: AGAP1 NM_001037131.3 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP1	NM_001037131.3	c.163+4A>T		splice_region_variant, intron_variant	Intron 1 of 17	ENST00000304032.13	NP_001032208.1
AGAP1	NM_014914.5	c.163+4A>T		splice_region_variant, intron_variant	Intron 1 of 16		NP_055729.2
AGAP1	NM_001244888.2	c.163+4A>T		splice_region_variant, intron_variant	Intron 1 of 9		NP_001231817.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP1	ENST00000304032.13	c.163+4A>T		splice_region_variant, intron_variant	Intron 1 of 17	5	NM_001037131.3	ENSP00000307634.7

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150516 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000579

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000519 AC: 11 AN: 211798 AF XY: 0.0000429

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000899

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000310

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000496 AC: 70 AN: 1411770 Hom.: 1 Cov.: 32 AF XY: 0.0000513 AC XY: 36 AN XY: 702362

African (AFR) AF: 0.00 AC: 0 AN: 29212

American (AMR) AF: 0.0000253 AC: 1 AN: 39458

Ashkenazi Jewish (ASJ) AF: 0.00106 AC: 26 AN: 24430

East Asian (EAS) AF: 0.00 AC: 0 AN: 33708

South Asian (SAS) AF: 0.00 AC: 0 AN: 82298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52332

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5590

European-Non Finnish (NFE) AF: 0.0000304 AC: 33 AN: 1086822

Other (OTH) AF: 0.000138 AC: 8 AN: 57920

GnomAD4 genome AF: 0.0000266 AC: 4 AN: 150516 Hom.: 0 Cov.: 29 AF XY: 0.0000408 AC XY: 3 AN XY: 73486

African (AFR) AF: 0.00 AC: 0 AN: 40966

American (AMR) AF: 0.00 AC: 0 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.000579 AC: 2 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5016

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67534

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.000158 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This sequence change falls in intron 1 of the AGAP1 gene. It does not directly change the encoded amino acid sequence of the AGAP1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200114461, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with AGAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1972441). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.97
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.15		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: rs200114461; hg19: chr2-236403497;