12-47748635-C-G

Variant names:

• chr12-47748635-C-G
• rs757281
• NM_001098531.4:c.1155-93G>C

Variant summary

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

The NM_001098531.4(RAPGEF3):​c.1155-93G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.808 in 1,239,608 control chromosomes in the GnomAD database, including 406,220 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 0.80 (49216 hom., cov: 32)
  • Exomes 𝑓: 0.81 (357004 hom.)
• Consequence: RAPGEF3 NM_001098531.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.717
• Publications: 7 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4	c.1155-93G>C		intron_variant	Intron 11 of 27	ENST00000449771.7	NP_001092001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.1155-93G>C		intron_variant	Intron 11 of 27	2	NM_001098531.4	ENSP00000395708.2
RAPGEF3	ENST00000389212.7	c.1155-93G>C		intron_variant	Intron 12 of 28	2		ENSP00000373864.3
RAPGEF3	ENST00000549151.5	c.1029-93G>C		intron_variant	Intron 11 of 27	5		ENSP00000448619.1
RAPGEF3	ENST00000548919.5	c.1029-93G>C		intron_variant	Intron 11 of 26	2		ENSP00000448480.1
RAPGEF3	ENST00000395358.7	c.1155-93G>C		intron_variant	Intron 11 of 15	2		ENSP00000378764.3
RAPGEF3	ENST00000495465.6	n.*272-93G>C		intron_variant	Intron 6 of 8	3		ENSP00000449818.1
RAPGEF3	ENST00000547856.5	n.*463-93G>C		intron_variant	Intron 7 of 23	2		ENSP00000449905.1

Frequencies

GnomAD3 genomes AF: 0.803 AC: 122027 AN: 152026 Hom.: 49162 Cov.: 32

Gnomad AFR AF: 0.775

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.941

Gnomad SAS AF: 0.724

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.816

Gnomad OTH AF: 0.808

GnomAD4 exome AF: 0.808 AC: 879053 AN: 1087464 Hom.: 357004 Cov.: 14 AF XY: 0.804 AC XY: 442169 AN XY: 550194

African (AFR) AF: 0.773 AC: 20208 AN: 26158

American (AMR) AF: 0.876 AC: 31921 AN: 36458

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 17753 AN: 21428

East Asian (EAS) AF: 0.918 AC: 34081 AN: 37106

South Asian (SAS) AF: 0.698 AC: 50484 AN: 72352

European-Finnish (FIN) AF: 0.733 AC: 36943 AN: 50392

Middle Eastern (MID) AF: 0.715 AC: 3538 AN: 4946

European-Non Finnish (NFE) AF: 0.816 AC: 645767 AN: 791050

Other (OTH) AF: 0.806 AC: 38358 AN: 47574

GnomAD4 genome AF: 0.803 AC: 122143 AN: 152144 Hom.: 49216 Cov.: 32 AF XY: 0.800 AC XY: 59464 AN XY: 74376

African (AFR) AF: 0.775 AC: 32145 AN: 41470

American (AMR) AF: 0.857 AC: 13111 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 2868 AN: 3472

East Asian (EAS) AF: 0.941 AC: 4862 AN: 5168

South Asian (SAS) AF: 0.724 AC: 3492 AN: 4826

European-Finnish (FIN) AF: 0.719 AC: 7612 AN: 10588

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.816 AC: 55504 AN: 68006

Other (OTH) AF: 0.811 AC: 1712 AN: 2112

Alfa AF: 0.772 Hom.: 2355

Bravo AF: 0.816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.20
DANN	Benign	0.54
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757281; hg19: chr12-48142418;