rs494453

Positions:

• chr1-111649500-T-C

Variant summary

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

The NM_002884.4(RAP1A):​c.-28+29566T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 299,118 control chromosomes in the GnomAD database, including 24,769 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 0.41 (12784 hom., cov: 32)
  • Exomes 𝑓: 0.40 (11985 hom.)
• Consequence: RAP1A NM_002884.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.155

Genes affected

RAP1A (HGNC:9855): (RAP1A, member of RAS oncogene family) This gene encodes a member of the Ras family of small GTPases. The encoded protein undergoes a change in conformational state and activity, depending on whether it is bound to GTP or GDP. This protein is activated by several types of guanine nucleotide exchange factors (GEFs), and inactivated by two groups of GTPase-activating proteins (GAPs). The activation status of the encoded protein is therefore affected by the balance of intracellular levels of GEFs and GAPs. The encoded protein regulates signaling pathways that affect cell proliferation and adhesion, and may play a role in tumor malignancy. Pseudogenes of this gene have been defined on chromosomes 14 and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

KRT18P57 (HGNC:48884): (keratin 18 pseudogene 57)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAP1A	NM_002884.4	c.-28+29566T>C		intron_variant		ENST00000369709.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAP1A	ENST00000369709.4	c.-28+29566T>C		intron_variant		1	NM_002884.4	P1
KRT18P57	ENST00000443599.2	n.45A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61981 AN: 151918 Hom.: 12766 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.388

GnomAD4 exome AF: 0.399 AC: 58681 AN: 147082 Hom.: 11985 Cov.: 0 AF XY: 0.394 AC XY: 32541 AN XY: 82560

Gnomad4 AFR exome AF: 0.471

Gnomad4 AMR exome AF: 0.526

Gnomad4 ASJ exome AF: 0.405

Gnomad4 EAS exome AF: 0.429

Gnomad4 SAS exome AF: 0.396

Gnomad4 FIN exome AF: 0.465

Gnomad4 NFE exome AF: 0.366

Gnomad4 OTH exome AF: 0.390

GnomAD4 genome AF: 0.408 AC: 62037 AN: 152036 Hom.: 12784 Cov.: 32 AF XY: 0.411 AC XY: 30510 AN XY: 74300

Gnomad4 AFR AF: 0.461

Gnomad4 AMR AF: 0.427

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.376

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.391

Alfa AF: 0.332 Hom.: 3998

Bravo AF: 0.409

Asia WGS AF: 0.459 AC: 1597 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.2
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs494453; hg19: chr1-112192122;