rs138785106

Variant names:

• chr5-87379850-C-T
• rs138785106
• NM_002890.3:c.2603C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_002890.3(RASA1):​c.2603C>T​(p.Pro868Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000906 in 1,611,544 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P868T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: RASA1 NM_002890.3 missense, splice_region
• Scores: Splicing: ADA: 0.6915
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 6.05
• Publications: 8 publications found

Genes affected

RASA1 (HGNC:9871): (RAS p21 protein activator 1) The protein encoded by this gene is located in the cytoplasm and is part of the GAP1 family of GTPase-activating proteins. The gene product stimulates the GTPase activity of normal RAS p21 but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Mutations also have been associated with hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM) and Parkes Weber syndrome. Alternative splicing results in two isoforms where the shorter isoform, lacking the N-terminal hydrophobic region but retaining the same activity, appears to be abundantly expressed in placental but not adult tissues. [provided by RefSeq, May 2012]

CCNH (HGNC:1594): (cyclin H) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with CDK7 kinase and ring finger protein MAT1. The kinase complex is able to phosphorylate CDK2 and CDC2 kinases, thus functions as a CDK-activating kinase (CAK). This cyclin and its kinase partner are components of TFIIH, as well as RNA polymerase II protein complexes. They participate in two different transcriptional regulation processes, suggesting an important link between basal transcription control and the cell cycle machinery. A pseudogene of this gene is found on chromosome 4. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Nov 2010]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 5-87379850-C-T is Benign according to our data. Variant chr5-87379850-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 354525.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000092 (14/152182) while in subpopulation EAS AF = 0.000193 (1/5180). AF 95% confidence interval is 0.0000955. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 14 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002890.3. 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
	RASA1	NM_002890.3	MANE Select	c.2603C>T	p.Pro868Leu	missense splice_region	Exon 19 of 25	NP_002881.1
	RASA1	NM_022650.3		c.2072C>T	p.Pro691Leu	missense splice_region	Exon 19 of 25	NP_072179.1
	CCNH	NM_001364075.2		c.933+15194G>A		intron	N/A	NP_001351004.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA1	ENST00000274376.11	TSL:1 MANE Select	c.2603C>T	p.Pro868Leu	missense splice_region	Exon 19 of 25	ENSP00000274376.6
	RASA1	ENST00000456692.6	TSL:1	c.2072C>T	p.Pro691Leu	missense splice_region	Exon 19 of 25	ENSP00000411221.2
	RASA1	ENST00000515800.6	TSL:1	n.*1128C>T		splice_region non_coding_transcript_exon	Exon 20 of 26	ENSP00000423395.2

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000760 AC: 19 AN: 249846 AF XY: 0.0000814

Gnomad AFR exome AF: 0.0000622

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: 0.000133

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000905 AC: 132 AN: 1459362 Hom.: 0 Cov.: 30 AF XY: 0.0000895 AC XY: 65 AN XY: 726088

African (AFR) AF: 0.0000899 AC: 3 AN: 33388

American (AMR) AF: 0.0000896 AC: 4 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39450

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000104 AC: 115 AN: 1110298

Other (OTH) AF: 0.0000995 AC: 6 AN: 60274

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74404

African (AFR) AF: 0.000193 AC: 8 AN: 41538

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3472

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jan 12, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the RASA1 gene. Although the P868L variant has not been published as pathogenic or been reported as benign to our knowledge, it has been classified as a variant of uncertain significance by another clinical laboratory in ClinVar (SCV000552994.1; Landrum et al., 2016). This variant is observed in 15/125,660 alleles (0.012%) from individuals of European (Non-Finnish) ancestry in large population cohorts (Lek et al., 2016). This nucleotide substitution (c.2603 C>T) occurs at the last nucleotide of exon 19, a position at which nucleotide substitutions commonly result in abnormal gene splicing (Buratti et al., 2007). Nevertheless, several in silico splice predictions models predict that the c.2603 C>T substitution does not cause abnormal gene splicing. Additionally, although the P868L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function.

Capillary malformation-arteriovenous malformation syndrome Uncertain:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 868 of the RASA1 protein (p.Pro868Leu). This variant is present in population databases (rs138785106, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with RASA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 354525). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Parkes Weber syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Capillary malformation-arteriovenous malformation 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Benign	0.93
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
PhyloP100		6.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.26
Sift	Benign	0.53	T
Sift4G	Benign	0.15	T
Polyphen		0.91	P
Vest4		0.71
MVP		0.83
MPC		1.8
ClinPred		0.16	T
GERP RS		5.0
Varity_R		0.39
gMVP		0.85
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
dbscSNV1_RF	Benign	0.42
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: rs138785106; hg19: chr5-86675667; COSMIC: COSV57203498; COSMIC: COSV57203498;