rs140707293

Variant names:

• chr5-87362589-G-A
• rs140707293
• NM_002890.3:c.1371G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_002890.3(RASA1):​c.1371G>A​(p.Lys457Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,596,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: RASA1 NM_002890.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.43
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 5-87362589-G-A is Benign according to our data. Variant chr5-87362589-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00188 (286/152164) while in subpopulation AFR AF = 0.00643 (267/41532). AF 95% confidence interval is 0.00579. There are 0 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 286 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.1371G>A	p.Lys457Lys	synonymous	Exon 10 of 25	NP_002881.1	P20936-1
	RASA1	NM_022650.3		c.840G>A	p.Lys280Lys	synonymous	Exon 10 of 25	NP_072179.1	P20936-2
	CCNH	NM_001364075.2		c.933+32455C>T		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.1371G>A	p.Lys457Lys	synonymous	Exon 10 of 25	ENSP00000274376.6	P20936-1
	RASA1	ENST00000456692.6	TSL:1	c.840G>A	p.Lys280Lys	synonymous	Exon 10 of 25	ENSP00000411221.2	P20936-2
	RASA1	ENST00000515800.6	TSL:1	n.1371G>A		non_coding_transcript_exon	Exon 10 of 26	ENSP00000423395.2	P20936-3

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00640

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

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: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000451 AC: 113 AN: 250830 AF XY: 0.000317

Gnomad AFR exome AF: 0.00652

Gnomad AMR exome AF: 0.000145

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: 0.000327

GnomAD4 exome AF: 0.000179 AC: 259 AN: 1444826 Hom.: 0 Cov.: 30 AF XY: 0.000140 AC XY: 101 AN XY: 720002

African (AFR) AF: 0.00681 AC: 225 AN: 33052

American (AMR) AF: 0.000291 AC: 13 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096638

Other (OTH) AF: 0.000300 AC: 18 AN: 59930

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74390

African (AFR) AF: 0.00643 AC: 267 AN: 41532

American (AMR) AF: 0.000916 AC: 14 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67966

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000752 Hom.: 0

Bravo AF: 0.00199

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Capillary malformation-arteriovenous malformation 1 (1)
-	-	1	Capillary malformation-arteriovenous malformation syndrome (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Parkes Weber syndrome (1)
-	-	1	RASA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.1
DANN	Benign	0.58
PhyloP100		1.4

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: rs140707293; hg19: chr5-86658406; COSMIC: COSV99169950;