1-21616643-C-T

Variant names:

• chr1-21616643-C-T
• rs829417
• NM_002885.4:c.291+663G>A

Variant summary

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

The NM_002885.4(RAP1GAP):​c.291+663G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 152,106 control chromosomes in the GnomAD database, including 7,267 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 0.31 (7267 hom., cov: 33)
• Consequence: RAP1GAP NM_002885.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.691
• Publications: 4 publications found

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002885.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1GAP	NM_002885.4	MANE Select	c.291+663G>A		intron	N/A	NP_002876.2
	RAP1GAP	NM_001388200.1		c.291+663G>A		intron	N/A	NP_001375129.1
	RAP1GAP	NM_001388201.1		c.291+663G>A		intron	N/A	NP_001375130.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1GAP	ENST00000374765.9	TSL:1 MANE Select	c.291+663G>A		intron	N/A	ENSP00000363897.4
	RAP1GAP	ENST00000374763.6	TSL:1	c.291+663G>A		intron	N/A	ENSP00000363895.2
	RAP1GAP	ENST00000495204.5	TSL:1	c.483+663G>A		intron	N/A	ENSP00000434033.2

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46902 AN: 151988 Hom.: 7257 Cov.: 33

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.309 AC: 46931 AN: 152106 Hom.: 7267 Cov.: 33 AF XY: 0.308 AC XY: 22894 AN XY: 74374

African (AFR) AF: 0.286 AC: 11844 AN: 41478

American (AMR) AF: 0.372 AC: 5690 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 708 AN: 3470

East Asian (EAS) AF: 0.252 AC: 1306 AN: 5178

South Asian (SAS) AF: 0.364 AC: 1754 AN: 4822

European-Finnish (FIN) AF: 0.285 AC: 3016 AN: 10588

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21580 AN: 67968

Other (OTH) AF: 0.284 AC: 601 AN: 2114

Alfa AF: 0.317 Hom.: 13132

Bravo AF: 0.316

Asia WGS AF: 0.302 AC: 1050 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.3
DANN	Benign	0.72
PhyloP100		-0.69
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: rs829417; hg19: chr1-21943136;