rs13157168

Variant names:

• chr5-87331321-G-A
• rs13157168
• NM_002890.3:c.540-27G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000274376.11(RASA1):​c.540-27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,572,704 control chromosomes in the GnomAD database, including 909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (43 hom., cov: 32)
  • Exomes 𝑓: 0.031 (866 hom.)
• Consequence: RASA1 ENST00000274376.11 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.666
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-87331321-G-A is Benign according to our data. Variant chr5-87331321-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 561432.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0202 (3073/152214) while in subpopulation NFE AF = 0.0338 (2300/68002). AF 95% confidence interval is 0.0327. There are 43 homozygotes in GnomAd4. There are 1402 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3073 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000274376.11. 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.540-27G>A		intron	N/A	NP_002881.1
	RASA1	NM_022650.3		c.9-27G>A		intron	N/A	NP_072179.1
	CCNH	NM_001364075.2		c.934-18526C>T		intron	N/A	NP_001351004.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RASA1	ENST00000274376.11	TSL:1 MANE Select	c.540-27G>A		intron	N/A	ENSP00000274376.6
	RASA1	ENST00000456692.6	TSL:1	c.9-27G>A		intron	N/A	ENSP00000411221.2
	RASA1	ENST00000515800.6	TSL:1	n.540-27G>A		intron	N/A	ENSP00000423395.2

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3073 AN: 152096 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.00570

Gnomad AMI AF: 0.0451

Gnomad AMR AF: 0.00773

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0338

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0209 AC: 5219 AN: 250054 AF XY: 0.0212

Gnomad AFR exome AF: 0.00524

Gnomad AMR exome AF: 0.00482

Gnomad ASJ exome AF: 0.00469

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0352

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0313 AC: 44458 AN: 1420490 Hom.: 866 Cov.: 30 AF XY: 0.0307 AC XY: 21782 AN XY: 708812

African (AFR) AF: 0.00435 AC: 141 AN: 32432

American (AMR) AF: 0.00498 AC: 222 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00557 AC: 144 AN: 25870

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39384

South Asian (SAS) AF: 0.0105 AC: 897 AN: 85334

European-Finnish (FIN) AF: 0.0254 AC: 1356 AN: 53356

Middle Eastern (MID) AF: 0.00580 AC: 33 AN: 5688

European-Non Finnish (NFE) AF: 0.0375 AC: 40257 AN: 1074870

Other (OTH) AF: 0.0238 AC: 1407 AN: 59010

GnomAD4 genome AF: 0.0202 AC: 3073 AN: 152214 Hom.: 43 Cov.: 32 AF XY: 0.0188 AC XY: 1402 AN XY: 74428

African (AFR) AF: 0.00568 AC: 236 AN: 41538

American (AMR) AF: 0.00772 AC: 118 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4818

European-Finnish (FIN) AF: 0.0252 AC: 267 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0338 AC: 2300 AN: 68002

Other (OTH) AF: 0.0128 AC: 27 AN: 2116

Alfa AF: 0.0271 Hom.: 106

Bravo AF: 0.0179

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.4
DANN	Benign	0.76
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

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: rs13157168; hg19: chr5-86627138; COSMIC: COSV107279350;