chr5-87268660-A-G

Position:

• chr5-87268660-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002890.3(RASA1):​c.209A>G​(p.Glu70Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,610,944 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (17 hom.)
• Consequence: RASA1 NM_002890.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.272

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RASA1. . Gene score misZ 3.0984 (greater than the threshold 3.09). Trascript score misZ 3.5912 (greater than threshold 3.09). GenCC has associacion of gene with capillary malformation-arteriovenous malformation syndrome, Parkes Weber syndrome, Noonan syndrome, telangiectasia, hereditary hemorrhagic, type 1, capillary malformation-arteriovenous malformation 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029049218).
• BP6: Variant 5-87268660-A-G is Benign according to our data. Variant chr5-87268660-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 354504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-87268660-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00274 (417/152196) while in subpopulation EAS AF= 0.00813 (42/5164). AF 95% confidence interval is 0.00618. There are 5 homozygotes in gnomad4. There are 305 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASA1	NM_002890.3	c.209A>G	p.Glu70Gly	missense_variant	1/25	ENST00000274376.11	NP_002881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASA1	ENST00000274376.11	c.209A>G	p.Glu70Gly	missense_variant	1/25	1	NM_002890.3	ENSP00000274376.6
RASA1	ENST00000515800.6	n.209A>G		non_coding_transcript_exon_variant	1/26	1		ENSP00000423395.2

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152078 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00811

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0295

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00363 AC: 876 AN: 241008 Hom.: 6 AF XY: 0.00362 AC XY: 474 AN XY: 130902

Gnomad AFR exome AF: 0.000600

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00957

Gnomad SAS exome AF: 0.000733

Gnomad FIN exome AF: 0.0275

Gnomad NFE exome AF: 0.000795

Gnomad OTH exome AF: 0.00273

GnomAD4 exome AF: 0.00170 AC: 2478 AN: 1458748 Hom.: 17 Cov.: 32 AF XY: 0.00167 AC XY: 1214 AN XY: 725386

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000294

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0149

Gnomad4 SAS exome AF: 0.000828

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.000408

Gnomad4 OTH exome AF: 0.00155

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152196 Hom.: 5 Cov.: 32 AF XY: 0.00410 AC XY: 305 AN XY: 74410

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00813

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0295

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000769 Hom.: 0

Bravo AF: 0.000771

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00324 AC: 393

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	RASA1: BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 07, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2018	- -

Capillary malformation-arteriovenous malformation syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Parkes Weber syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2024

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Capillary malformation-arteriovenous malformation 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.73
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.059
Sift	Benign	1.0	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.052
MVP		0.39
MPC		0.065
ClinPred		0.0026	T
GERP RS		2.4
Varity_R		0.041
gMVP		0.30

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: rs146525982; hg19: chr5-86564477;