NM_002890.3:c.2773A>G

Variant names:

• chr5-87385315-A-G
• rs140786299
• NM_002890.3:c.2773A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_002890.3(RASA1):​c.2773A>G​(p.Ile925Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000373 in 1,608,966 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: RASA1 NM_002890.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 5.95
• Publications: 3 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09488648).
• BP6: Variant 5-87385315-A-G is Benign according to our data. Variant chr5-87385315-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533443.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000105 (16/152032) while in subpopulation AMR AF = 0.000525 (8/15250). AF 95% confidence interval is 0.000261. There are 1 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 16 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA1	NM_002890.3	MANE Select	c.2773A>G	p.Ile925Val	missense	Exon 22 of 25	NP_002881.1	P20936-1
	RASA1	NM_022650.3		c.2242A>G	p.Ile748Val	missense	Exon 22 of 25	NP_072179.1	P20936-2
	CCNH	NM_001364075.2		c.933+9729T>C		intron	N/A	NP_001351004.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA1	ENST00000274376.11	TSL:1 MANE Select	c.2773A>G	p.Ile925Val	missense	Exon 22 of 25	ENSP00000274376.6	P20936-1
	RASA1	ENST00000456692.6	TSL:1	c.2242A>G	p.Ile748Val	missense	Exon 22 of 25	ENSP00000411221.2	P20936-2
	RASA1	ENST00000515800.6	TSL:1	n.*1298A>G		non_coding_transcript_exon	Exon 23 of 26	ENSP00000423395.2	P20936-3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152032 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 250464 AF XY: 0.0000443

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000302 AC: 44 AN: 1456934 Hom.: 0 Cov.: 30 AF XY: 0.0000372 AC XY: 27 AN XY: 725074

African (AFR) AF: 0.0000300 AC: 1 AN: 33322

American (AMR) AF: 0.00 AC: 0 AN: 44654

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.0000280 AC: 31 AN: 1107850

Other (OTH) AF: 0.000166 AC: 10 AN: 60204

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152032 Hom.: 1 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74266

African (AFR) AF: 0.0000483 AC: 2 AN: 41436

American (AMR) AF: 0.000525 AC: 8 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67930

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000305 Hom.: 0

Bravo AF: 0.0000831

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Capillary malformation-arteriovenous malformation 1 (1)
-	1	-	Capillary malformation-arteriovenous malformation syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	RASA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.030
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.095	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-1.2	N
PhyloP100		5.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.41	N
REVEL	Uncertain	0.30
Sift	Benign	0.52	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.61
MPC		0.63
ClinPred		0.075	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.17
Mutation Taster		=75/25	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: rs140786299; hg19: chr5-86681132; COSMIC: COSV105096108;