2-172861531-G-A

Variant names:

• chr2-172861531-G-A
• rs3769292
• NM_007023.4:c.444+47106G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007023.4(RAPGEF4):​c.444+47106G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0957 in 152,226 control chromosomes in the GnomAD database, including 713 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 0.096 (713 hom., cov: 33)
• Consequence: RAPGEF4 NM_007023.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• Publications: 4 publications found

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]

RAPGEF4 Gene-Disease associations (from GenCC):

• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF4	NM_007023.4	c.444+47106G>A		intron_variant	Intron 4 of 30	ENST00000397081.8	NP_008954.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF4	ENST00000397081.8	c.444+47106G>A		intron_variant	Intron 4 of 30	1	NM_007023.4	ENSP00000380271.3
RAPGEF4	ENST00000409036.5	c.444+47106G>A		intron_variant	Intron 4 of 27	5		ENSP00000387104.1

Frequencies

GnomAD3 genomes AF: 0.0956 AC: 14537 AN: 152108 Hom.: 706 Cov.: 33

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0682

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0955

Gnomad OTH AF: 0.0957

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

GnomAD4 genome AF: 0.0957 AC: 14563 AN: 152226 Hom.: 713 Cov.: 33 AF XY: 0.0965 AC XY: 7179 AN XY: 74428

African (AFR) AF: 0.0862 AC: 3582 AN: 41534

American (AMR) AF: 0.112 AC: 1706 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3470

East Asian (EAS) AF: 0.117 AC: 604 AN: 5182

South Asian (SAS) AF: 0.148 AC: 713 AN: 4822

European-Finnish (FIN) AF: 0.0682 AC: 723 AN: 10606

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0955 AC: 6497 AN: 68006

Other (OTH) AF: 0.103 AC: 217 AN: 2112

Alfa AF: 0.0937 Hom.: 336

Bravo AF: 0.0954

Asia WGS AF: 0.163 AC: 568 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.1
DANN	Benign	0.37
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs3769292; hg19: chr2-173726259;