chr2-172957934-G-A

Variant names:

• chr2-172957934-G-A
• rs3769249
• NM_007023.4:c.538-2826G>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.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
• Publications: 2 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=-0.85).
• 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 rank	MANE	Protein	UniProt
RAPGEF4	NM_007023.4	c.538-2826G>A		intron_variant	Intron 6 of 30	ENST00000397081.8	NP_008954.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF4	ENST00000397081.8	c.538-2826G>A		intron_variant	Intron 6 of 30	1	NM_007023.4	ENSP00000380271.3
RAPGEF4	ENST00000409036.5	c.538-2826G>A		intron_variant	Intron 6 of 27	5		ENSP00000387104.1

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

African (AFR) AF: 0.269 AC: 11178 AN: 41510

American (AMR) AF: 0.459 AC: 7020 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1412 AN: 3468

East Asian (EAS) AF: 0.457 AC: 2363 AN: 5166

South Asian (SAS) AF: 0.455 AC: 2195 AN: 4820

European-Finnish (FIN) AF: 0.364 AC: 3848 AN: 10582

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.406 AC: 27575 AN: 67996

Other (OTH) AF: 0.409 AC: 865 AN: 2114

Alfa AF: 0.396 Hom.: 12236

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
PhyloP100		-0.077
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: rs3769249; hg19: chr2-173822662;