1-21598035-C-T

Variant names:

• chr1-21598035-C-T
• rs777993196
• NM_002885.4:c.1909G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002885.4(RAP1GAP):​c.1909G>A​(p.Gly637Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000907 in 1,543,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: RAP1GAP NM_002885.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.210

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13076296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAP1GAP	NM_002885.4	c.1909G>A	p.Gly637Ser	missense_variant	Exon 23 of 25	ENST00000374765.9	NP_002876.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAP1GAP	ENST00000374765.9	c.1909G>A	p.Gly637Ser	missense_variant	Exon 23 of 25	1	NM_002885.4	ENSP00000363897.4

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150634 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.0000147 AC: 3 AN: 204288 AF XY: 0.0000181

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000335

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000790 AC: 11 AN: 1393274 Hom.: 0 Cov.: 33 AF XY: 0.00000724 AC XY: 5 AN XY: 690258

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31930

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 39462

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 36686

Gnomad4 SAS exome AF: 0.0000122 AC: 1 AN: 81784

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 45986

Gnomad4 NFE exome AF: 0.00000839 AC: 9 AN: 1072568

Gnomad4 Remaining exome AF: 0.0000176 AC: 1 AN: 56658

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150634 Hom.: 0 Cov.: 33 AF XY: 0.0000272 AC XY: 2 AN XY: 73534

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.000289 AC: 0.000289352 AN: 0.000289352

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000148 AC: 0.0000147776 AN: 0.0000147776

Gnomad4 OTH AF: 0.000482 AC: 0.000481696 AN: 0.000481696

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000332 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2101G>A (p.G701S) alteration is located in exon 23 (coding exon 23) of the RAP1GAP gene. This alteration results from a G to A substitution at nucleotide position 2101, causing the glycine (G) at amino acid position 701 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.0078	.;T;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.2	.;.;L;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.080	.;N;N;N;.
REVEL	Uncertain	0.35
Sift	Benign	0.26	.;T;T;T;.
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.0060, 0.0010	.;.;B;B;.
Vest4		0.23
MutPred		0.091		.;.;Gain of glycosylation at G637 (P = 0.0053);.;.;
MVP		0.30
ClinPred		0.28	T
GERP RS		-1.3
Varity_R		0.094
gMVP		0.14
Mutation Taster		=93/7	polymorphism

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: rs777993196; hg19: chr1-21924528;