chr12-47751585-A-G

Variant names:

• chr12-47751585-A-G
• rs2072115
• NM_001098531.4:c.381-65T>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.381-65T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,606,848 control chromosomes in the GnomAD database, including 45,903 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 0.23 (4027 hom., cov: 33)
  • Exomes 𝑓: 0.24 (41876 hom.)
• Consequence: RAPGEF3 NM_001098531.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.310
• Publications: 16 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4	c.381-65T>C		intron_variant	Intron 4 of 27	ENST00000449771.7	NP_001092001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.381-65T>C		intron_variant	Intron 4 of 27	2	NM_001098531.4	ENSP00000395708.2
RAPGEF3	ENST00000389212.7	c.381-65T>C		intron_variant	Intron 5 of 28	2		ENSP00000373864.3
RAPGEF3	ENST00000549151.5	c.255-65T>C		intron_variant	Intron 4 of 27	5		ENSP00000448619.1
RAPGEF3	ENST00000548919.5	c.255-65T>C		intron_variant	Intron 4 of 26	2		ENSP00000448480.1
RAPGEF3	ENST00000395358.7	c.381-65T>C		intron_variant	Intron 4 of 15	2		ENSP00000378764.3
RAPGEF3	ENST00000547856.5	n.220-1160T>C		intron_variant	Intron 2 of 23	2		ENSP00000449905.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34583 AN: 152122 Hom.: 4026 Cov.: 33

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.252

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.235 AC: 341994 AN: 1454608 Hom.: 41876 Cov.: 37 AF XY: 0.232 AC XY: 167987 AN XY: 722566

African (AFR) AF: 0.226 AC: 7541 AN: 33316

American (AMR) AF: 0.139 AC: 6200 AN: 44524

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 6476 AN: 25884

East Asian (EAS) AF: 0.130 AC: 5137 AN: 39564

South Asian (SAS) AF: 0.137 AC: 11767 AN: 85914

European-Finnish (FIN) AF: 0.178 AC: 9466 AN: 53040

Middle Eastern (MID) AF: 0.254 AC: 1459 AN: 5744

European-Non Finnish (NFE) AF: 0.253 AC: 279791 AN: 1106582

Other (OTH) AF: 0.236 AC: 14157 AN: 60040

GnomAD4 genome AF: 0.227 AC: 34583 AN: 152240 Hom.: 4027 Cov.: 33 AF XY: 0.220 AC XY: 16401 AN XY: 74436

African (AFR) AF: 0.230 AC: 9536 AN: 41530

American (AMR) AF: 0.196 AC: 2998 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3472

East Asian (EAS) AF: 0.139 AC: 719 AN: 5178

South Asian (SAS) AF: 0.132 AC: 638 AN: 4826

European-Finnish (FIN) AF: 0.182 AC: 1932 AN: 10616

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17128 AN: 68002

Other (OTH) AF: 0.243 AC: 513 AN: 2114

Alfa AF: 0.236 Hom.: 11530

Bravo AF: 0.227

Asia WGS AF: 0.129 AC: 446 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	1.3
DANN	Benign	0.58
PhyloP100		-0.31
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: rs2072115; hg19: chr12-48145368; COSMIC: COSV50254897; COSMIC: COSV50254897;