rs494453

Variant names:

• chr1-111649500-T-C
• rs494453
• NM_002884.4:c.-28+29566T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 32 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002884.4. 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
	RAP1A	NM_002884.4	MANE Select	c.-28+29566T>C		intron	N/A	NP_002875.1
	RAP1A	NM_001010935.3		c.-28+21937T>C		intron	N/A	NP_001010935.1
	RAP1A	NM_001291896.3		c.-28+29153T>C		intron	N/A	NP_001278825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1A	ENST00000369709.4	TSL:1 MANE Select	c.-28+29566T>C		intron	N/A	ENSP00000358723.3
	RAP1A	ENST00000356415.5	TSL:1	c.-27-41834T>C		intron	N/A	ENSP00000348786.1
	KRT18P57	ENST00000443599.2	TSL:6	n.45A>G		non_coding_transcript_exon	Exon 1 of 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

African (AFR) AF: 0.471 AC: 1810 AN: 3844

American (AMR) AF: 0.526 AC: 7339 AN: 13960

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1126 AN: 2782

East Asian (EAS) AF: 0.429 AC: 2984 AN: 6958

South Asian (SAS) AF: 0.396 AC: 8434 AN: 21284

European-Finnish (FIN) AF: 0.465 AC: 4029 AN: 8668

Middle Eastern (MID) AF: 0.348 AC: 135 AN: 388

European-Non Finnish (NFE) AF: 0.366 AC: 30132 AN: 82304

Other (OTH) AF: 0.390 AC: 2692 AN: 6894

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

African (AFR) AF: 0.461 AC: 19130 AN: 41476

American (AMR) AF: 0.427 AC: 6520 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1423 AN: 3468

East Asian (EAS) AF: 0.439 AC: 2266 AN: 5160

South Asian (SAS) AF: 0.376 AC: 1810 AN: 4812

European-Finnish (FIN) AF: 0.474 AC: 5001 AN: 10552

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24665 AN: 67962

Other (OTH) AF: 0.391 AC: 828 AN: 2116

Alfa AF: 0.334 Hom.: 4160

Bravo AF: 0.409

Asia WGS AF: 0.459 AC: 1597 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	7.2
DANN	Benign	0.38
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs494453; hg19: chr1-112192122;