rs3769249

Positions:

• chr2-172957934-G-A
• chr2-172957934-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007023.4(RAPGEF4):​c.538-2826G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 152,148 control chromosomes in the GnomAD database, including 11,108 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.37 (11108 hom., cov: 33)
• Consequence: RAPGEF4 NM_007023.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0770

Genes affected

RAPGEF4 (HGNC:16626): (Rap guanine nucleotide exchange factor 4) Enables guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of neurotransmitter receptor localization to postsynaptic specialization membrane and regulation of postsynapse organization. Predicted to act upstream of or within adenylate cyclase-activating G protein-coupled receptor signaling pathway; regulation of exocytosis; and secretion by cell. Predicted to be located in plasma membrane. Predicted to be active in glutamatergic synapse; hippocampal mossy fiber to CA3 synapse; and postsynaptic density. Implicated in autistic disorder. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPGEF4	NM_007023.4	c.538-2826G>A		intron_variant		ENST00000397081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPGEF4	ENST00000397081.8	c.538-2826G>A		intron_variant		1	NM_007023.4	P1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56905 AN: 152030 Hom.: 11098 Cov.: 33

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.458

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.401

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.374 AC: 56950 AN: 152148 Hom.: 11108 Cov.: 33 AF XY: 0.373 AC XY: 27754 AN XY: 74392

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.459

Gnomad4 ASJ AF: 0.407

Gnomad4 EAS AF: 0.457

Gnomad4 SAS AF: 0.455

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.409

Alfa AF: 0.397 Hom.: 7506

Bravo AF: 0.377

Asia WGS AF: 0.491 AC: 1707 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.5
DANN	Benign	0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs3769249; hg19: chr2-173822662;