NM_002890.3:c.1102+10T>C

Variant names:

• chr5-87346734-T-C
• rs150779406
• NM_002890.3:c.1102+10T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002890.3(RASA1):​c.1102+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,527,266 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (14 hom.)
• Consequence: RASA1 NM_002890.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.52
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 5-87346734-T-C is Benign according to our data. Variant chr5-87346734-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 354514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00264 (402/152146) while in subpopulation EAS AF = 0.00811 (42/5180). AF 95% confidence interval is 0.00616. There are 5 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 402 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.1102+10T>C		intron	N/A	NP_002881.1
	RASA1	NM_022650.3		c.571+10T>C		intron	N/A	NP_072179.1
	CCNH	NM_001364075.2		c.934-33939A>G		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.1102+10T>C		intron	N/A	ENSP00000274376.6
	RASA1	ENST00000456692.6	TSL:1	c.571+10T>C		intron	N/A	ENSP00000411221.2
	RASA1	ENST00000515800.6	TSL:1	n.1102+10T>C		intron	N/A	ENSP00000423395.2

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152028 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00809

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00357 AC: 888 AN: 248564 AF XY: 0.00358

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00917

Gnomad FIN exome AF: 0.0268

Gnomad NFE exome AF: 0.000836

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00174 AC: 2396 AN: 1375120 Hom.: 14 Cov.: 24 AF XY: 0.00172 AC XY: 1187 AN XY: 688334

African (AFR) AF: 0.0000318 AC: 1 AN: 31454

American (AMR) AF: 0.000271 AC: 12 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25314

East Asian (EAS) AF: 0.0149 AC: 579 AN: 38826

South Asian (SAS) AF: 0.000836 AC: 70 AN: 83744

European-Finnish (FIN) AF: 0.0232 AC: 1229 AN: 52916

Middle Eastern (MID) AF: 0.000902 AC: 5 AN: 5546

European-Non Finnish (NFE) AF: 0.000403 AC: 417 AN: 1035760

Other (OTH) AF: 0.00145 AC: 83 AN: 57308

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152146 Hom.: 5 Cov.: 32 AF XY: 0.00397 AC XY: 295 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.000393 AC: 6 AN: 15262

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

East Asian (EAS) AF: 0.00811 AC: 42 AN: 5180

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.0293 AC: 311 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000560 AC: 38 AN: 67914

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000591 Hom.: 0

Bravo AF: 0.000608

Asia WGS AF: 0.0120 AC: 41 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Capillary malformation-arteriovenous malformation 1 (1)
-	-	1	Capillary malformation-arteriovenous malformation syndrome (1)
-	-	1	Parkes Weber syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.64
PhyloP100		1.5
Mutation Taster		=100/0	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: rs150779406; hg19: chr5-86642551; COSMIC: COSV57199671;