rs6426723

Positions:

• chr1-21662882-A-G

Variant summary

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

The ENST00000374765.9(RAP1GAP):​c.-149+6372T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 152,260 control chromosomes in the GnomAD database, including 230 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 0.053 (230 hom., cov: 32)
• Consequence: RAP1GAP ENST00000374765.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.598

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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0545 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAP1GAP	NM_002885.4	c.-149+6372T>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.-149+6372T>C		intron_variant		1	NM_002885.4	ENSP00000363897	A1

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8141 AN: 152142 Hom.: 230 Cov.: 32

Gnomad AFR AF: 0.0565

Gnomad AMI AF: 0.0606

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0572

Gnomad FIN AF: 0.0721

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0538

Gnomad OTH AF: 0.0540

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

GnomAD4 genome AF: 0.0535 AC: 8141 AN: 152260 Hom.: 230 Cov.: 32 AF XY: 0.0539 AC XY: 4014 AN XY: 74446

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.0405

Gnomad4 ASJ AF: 0.0850

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0564

Gnomad4 FIN AF: 0.0721

Gnomad4 NFE AF: 0.0538

Gnomad4 OTH AF: 0.0534

Alfa AF: 0.0505 Hom.: 92

Bravo AF: 0.0514

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.74
DANN	Benign	0.73

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: rs6426723; hg19: chr1-21989375;