1-21601327-C-G

Position:

• chr1-21601327-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002885.4(RAP1GAP):​c.1652+357G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 151,948 control chromosomes in the GnomAD database, including 21,813 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 0.53 (21813 hom., cov: 31)
• Consequence: RAP1GAP NM_002885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.240

Genes affected

RAP1GAP (HGNC:9858): (RAP1 GTPase activating protein) This gene encodes a type of GTPase-activating-protein (GAP) that down-regulates the activity of the ras-related RAP1 protein. RAP1 acts as a molecular switch by cycling between an inactive GDP-bound form and an active GTP-bound form. The product of this gene, RAP1GAP, promotes the hydrolysis of bound GTP and hence returns RAP1 to the inactive state whereas other proteins, guanine nucleotide exchange factors (GEFs), act as RAP1 activators by facilitating the conversion of RAP1 from the GDP- to the GTP-bound form. In general, ras subfamily proteins, such as RAP1, play key roles in receptor-linked signaling pathways that control cell growth and differentiation. RAP1 plays a role in diverse processes such as cell proliferation, adhesion, differentiation, and embryogenesis. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAP1GAP	NM_002885.4	c.1652+357G>C		intron_variant		ENST00000374765.9	NP_002876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAP1GAP	ENST00000374765.9	c.1652+357G>C		intron_variant		1	NM_002885.4	ENSP00000363897	A1

Frequencies

GnomAD3 genomes AF: 0.534 AC: 81086 AN: 151830 Hom.: 21805 Cov.: 31

Gnomad AFR AF: 0.505

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.549

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.534 AC: 81113 AN: 151948 Hom.: 21813 Cov.: 31 AF XY: 0.530 AC XY: 39378 AN XY: 74274

Gnomad4 AFR AF: 0.505

Gnomad4 AMR AF: 0.530

Gnomad4 ASJ AF: 0.641

Gnomad4 EAS AF: 0.413

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.531

Gnomad4 NFE AF: 0.564

Gnomad4 OTH AF: 0.542

Alfa AF: 0.403 Hom.: 1076

Bravo AF: 0.534

Asia WGS AF: 0.407 AC: 1415 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.5
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs4654973; hg19: chr1-21927820;