rs1010729751

Variant names:

• chr5-87268468-C-A
• rs1010729751
• NM_002890.3:c.17C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-87268468-C-A
• chr5-87268468-C-T

Variant summary

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

The NM_002890.3(RASA1):​c.17C>A​(p.Ala6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RASA1 NM_002890.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• Publications: 0 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]

RASA1 Gene-Disease associations (from GenCC):

• capillary malformation-arteriovenous malformation 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• capillary malformation-arteriovenous malformation syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Parkes Weber syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000303897 (HGNC:):

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=0.1608443).

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.17C>A	p.Ala6Asp	missense	Exon 1 of 25	NP_002881.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA1	ENST00000274376.11	TSL:1 MANE Select	c.17C>A	p.Ala6Asp	missense	Exon 1 of 25	ENSP00000274376.6
	RASA1	ENST00000515800.6	TSL:1	n.17C>A		non_coding_transcript_exon	Exon 1 of 26	ENSP00000423395.2
	ENSG00000303897	ENST00000797921.1		n.356G>T		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000653 AC: 1 AN: 153154 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398640 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 689724

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

African (AFR) AF: 0.00 AC: 0 AN: 31830

American (AMR) AF: 0.00 AC: 0 AN: 35728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25086

East Asian (EAS) AF: 0.00 AC: 0 AN: 36208

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079558

Other (OTH) AF: 0.00 AC: 0 AN: 57858

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.24
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.067	T
Polyphen		0.023	B
Vest4		0.52
MutPred		0.11		Gain of loop (P = 0.0312)
MVP		0.59
MPC		0.29
ClinPred		0.56	D
GERP RS		1.1
PromoterAI		-0.086	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.15
gMVP		0.54
Mutation Taster		=90/10	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

Other links and lift over

dbSNP: rs1010729751; hg19: chr5-86564285;