rs13157168

Positions:

• chr5-87331321-G-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3073 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASA1	NM_002890.3	c.540-27G>A		intron_variant		ENST00000274376.11	NP_002881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASA1	ENST00000274376.11	c.540-27G>A		intron_variant		1	NM_002890.3	ENSP00000274376	P2

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

GnomAD3 exomes AF: 0.0209 AC: 5219 AN: 250054 Hom.: 89 AF XY: 0.0212 AC XY: 2871 AN XY: 135160

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 SAS exome AF: 0.00973

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

Gnomad4 AFR exome AF: 0.00435

Gnomad4 AMR exome AF: 0.00498

Gnomad4 ASJ exome AF: 0.00557

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.0254

Gnomad4 NFE exome AF: 0.0375

Gnomad4 OTH exome AF: 0.0238

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

Gnomad4 AFR AF: 0.00568

Gnomad4 AMR AF: 0.00772

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0338

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0287 Hom.: 87

Bravo AF: 0.0179

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.4
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs13157168; hg19: chr5-86627138;