rs2074533

Variant names:

• chr12-47740912-T-A
• rs2074533
• NM_001098531.4:c.2049+3A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-47740912-T-A
• chr12-47740912-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001098531.4(RAPGEF3):​c.2049+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RAPGEF3 NM_001098531.4 splice_region, intron
• Scores: Splicing: ADA: 0.5427
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168

Genes affected

RAPGEF3 (HGNC:16629): (Rap guanine nucleotide exchange factor 3) Enables guanyl-nucleotide exchange factor activity and protein domain specific binding activity. Involved in several processes, including positive regulation of protein modification process; regulation of actin cytoskeleton organization; and regulation of syncytium formation by plasma membrane fusion. Located in filopodium; lamellipodium; and microvillus. Colocalizes with cortical actin cytoskeleton and plasma membrane. Biomarker of congestive heart failure. [provided by Alliance of Genome Resources, Apr 2022]

RPAP3-DT (HGNC:55477): (RPAP3 divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4	c.2049+3A>T		splice_region_variant, intron_variant	Intron 20 of 27	ENST00000449771.7	NP_001092001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.2049+3A>T		splice_region_variant, intron_variant	Intron 20 of 27	2	NM_001098531.4	ENSP00000395708.2
RAPGEF3	ENST00000389212.7	c.2049+3A>T		splice_region_variant, intron_variant	Intron 21 of 28	2		ENSP00000373864.3
RAPGEF3	ENST00000549151.5	c.1923+3A>T		splice_region_variant, intron_variant	Intron 20 of 27	5		ENSP00000448619.1
RAPGEF3	ENST00000548919.5	c.1776+3A>T		splice_region_variant, intron_variant	Intron 19 of 26	2		ENSP00000448480.1
RAPGEF3	ENST00000547856.5	n.*1357+3A>T		splice_region_variant, intron_variant	Intron 16 of 23	2		ENSP00000449905.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 82

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.54
dbscSNV1_RF	Benign	0.35
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.48		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2074533; hg19: chr12-48134695;