chr12-47737637-T-C

Position:

• chr12-47737637-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001098531.4(RAPGEF3):​c.2702A>G​(p.Tyr901Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,290 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAPGEF3 NM_001098531.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

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]

RAPGEF3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3514896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4	c.2702A>G	p.Tyr901Cys	missense_variant	28/28	ENST00000449771.7	NP_001092001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.2702A>G	p.Tyr901Cys	missense_variant	28/28	2	NM_001098531.4	ENSP00000395708.2
RAPGEF3	ENST00000389212.7	c.2702A>G	p.Tyr901Cys	missense_variant	29/29	2		ENSP00000373864.3
RAPGEF3	ENST00000549151.5	c.2576A>G	p.Tyr859Cys	missense_variant	28/28	5		ENSP00000448619.1
RAPGEF3	ENST00000548919.5	c.2375A>G	p.Tyr792Cys	missense_variant	27/27	2		ENSP00000448480.1
RAPGEF3	ENST00000547856.5	n.*2010A>G		non_coding_transcript_exon_variant	24/24	2		ENSP00000449905.1
RAPGEF3	ENST00000547856.5	n.*2010A>G		3_prime_UTR_variant	24/24	2		ENSP00000449905.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460290 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2024

The c.2702A>G (p.Y901C) alteration is located in exon 28 (coding exon 28) of the RAPGEF3 gene. This alteration results from a A to G substitution at nucleotide position 2702, causing the tyrosine (Y) at amino acid position 901 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;D;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	.;D;.;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.9	M;.;.;M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.6	D;D;D;D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;.;D;.
Vest4		0.32
MutPred		0.61		Gain of catalytic residue at V902 (P = 0.0159);.;.;Gain of catalytic residue at V902 (P = 0.0159);.;
MVP		0.60
MPC		0.31
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.58
gMVP		0.70

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-48131420;