12-47740985-A-T

Position:

• chr12-47740985-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001098531.4(RAPGEF3):​c.1979T>A​(p.Leu660Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00579 in 1,613,472 control chromosomes in the GnomAD database, including 427 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (215 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (212 hom.)
• Consequence: RAPGEF3 NM_001098531.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.11

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005127847).
• BP6: Variant 12-47740985-A-T is Benign according to our data. Variant chr12-47740985-A-T is described in ClinVar as [Benign]. Clinvar id is 785403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4	c.1979T>A	p.Leu660Gln	missense_variant	20/28	ENST00000449771.7	NP_001092001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.1979T>A	p.Leu660Gln	missense_variant	20/28	2	NM_001098531.4	ENSP00000395708	P4
RPAP3-DT	ENST00000547799.5	n.1990A>T		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4533 AN: 152188 Hom.: 214 Cov.: 33

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.00810 AC: 1993 AN: 246052 Hom.: 95 AF XY: 0.00585 AC XY: 781 AN XY: 133572

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.00591

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000628

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00329 AC: 4809 AN: 1461166 Hom.: 212 Cov.: 33 AF XY: 0.00286 AC XY: 2081 AN XY: 726822

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00690

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.00656

GnomAD4 genome AF: 0.0298 AC: 4541 AN: 152306 Hom.: 215 Cov.: 33 AF XY: 0.0287 AC XY: 2139 AN XY: 74468

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.00184 Hom.: 2

Bravo AF: 0.0337

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.100 AC: 441

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00943 AC: 1145

EpiCase AF: 0.000654

EpiControl AF: 0.000832

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.58	D;.;.;D;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.82	.;T;.;T;T
MetaRNN	Benign	0.0051	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.33	N;.;.;N;.
MutationTaster	Benign	0.013	P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Benign	0.077
Sift	Benign	0.060	T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.0070	B;.;.;B;.
Vest4		0.37
MVP		0.53
MPC		0.22
ClinPred		0.020	T
GERP RS		2.9
Varity_R		0.33
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80097705; hg19: chr12-48134768; COSMIC: COSV99060312; COSMIC: COSV99060312;