1-111697416-CTTTTTT-CTTTTTTT

Variant names:

• chr1-111697416-C-CT
• rs34219774
• NM_002884.4:c.127-11dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_002884.4(RAP1A):​c.127-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,552,866 control chromosomes in the GnomAD database, including 4,477 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4459 hom., cov: 22)
  • Exomes 𝑓: 0.16 (18 hom.)
• Consequence: RAP1A NM_002884.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.159
• Publications: 1 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]

INKA2 (HGNC:28045): (inka box actin regulator 2) Enables protein kinase binding activity. Predicted to be involved in negative regulation of catalytic activity. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-111697416-C-CT is Benign according to our data. Variant chr1-111697416-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1253450.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.369 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1A	NM_002884.4	MANE Select	c.127-11dupT		intron	N/A	NP_002875.1	P62834
	RAP1A	NM_001010935.3		c.127-11dupT		intron	N/A	NP_001010935.1	P62834
	RAP1A	NM_001291896.3		c.127-11dupT		intron	N/A	NP_001278825.1	P62834

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAP1A	ENST00000369709.4	TSL:1 MANE Select	c.127-25_127-24insT		intron	N/A	ENSP00000358723.3	P62834
	RAP1A	ENST00000356415.5	TSL:1	c.127-25_127-24insT		intron	N/A	ENSP00000348786.1	P62834
	RAP1A	ENST00000687939.1		c.127-25_127-24insT		intron	N/A	ENSP00000509234.1	P62834

Frequencies

GnomAD3 genomes AF: 0.241 AC: 34343 AN: 142388 Hom.: 4449 Cov.: 22

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.224

GnomAD2 exomes AF: 0.151 AC: 24993 AN: 165996 AF XY: 0.148

Gnomad AFR exome AF: 0.277

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.125

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.161 AC: 227013 AN: 1410432 Hom.: 18 Cov.: 0 AF XY: 0.158 AC XY: 110598 AN XY: 701854

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.268 AC: 8368 AN: 31186

American (AMR) AF: 0.0940 AC: 3803 AN: 40450

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2815 AN: 25002

East Asian (EAS) AF: 0.121 AC: 4680 AN: 38544

South Asian (SAS) AF: 0.116 AC: 9401 AN: 81030

European-Finnish (FIN) AF: 0.136 AC: 6543 AN: 48024

Middle Eastern (MID) AF: 0.177 AC: 979 AN: 5536

European-Non Finnish (NFE) AF: 0.167 AC: 181132 AN: 1082620

Other (OTH) AF: 0.160 AC: 9292 AN: 58040

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.241 AC: 34377 AN: 142434 Hom.: 4459 Cov.: 22 AF XY: 0.239 AC XY: 16547 AN XY: 69120

African (AFR) AF: 0.374 AC: 14643 AN: 39118

American (AMR) AF: 0.186 AC: 2631 AN: 14178

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 502 AN: 3328

East Asian (EAS) AF: 0.148 AC: 733 AN: 4948

South Asian (SAS) AF: 0.162 AC: 723 AN: 4466

European-Finnish (FIN) AF: 0.194 AC: 1645 AN: 8474

Middle Eastern (MID) AF: 0.205 AC: 57 AN: 278

European-Non Finnish (NFE) AF: 0.197 AC: 12797 AN: 64796

Other (OTH) AF: 0.225 AC: 443 AN: 1966

Alfa AF: 0.0728 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
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: rs34219774; hg19: chr1-112240038;