chr14-20693325-G-C

Position:

• chr14-20693325-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002937.5(RNASE4):​c.-17-6030G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 152,350 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.025 (66 hom., cov: 32)
• Consequence: RNASE4 NM_002937.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.18

Genes affected

ANG (HGNC:483): (angiogenin) The protein encoded by this gene is a member of the RNase A superfamily though it has relatively weak ribonucleolytic activity. This protein is a potent mediator of new blood vessel formation and thus, in addition to the name RNase5, is commonly called angiogenin. This protein induces angiogenesis after binding to actin on the surface of endothelial cells. This protein also accumulates at the nucleolus where it stimulates ribosomal transcription. Under stress conditions this protein translocates to the cytosol where it hydrolyzes cellular tRNAs and influences protein synthesis. A signal peptide is cleaved from the precursor protein to produce a mature protein which contains a nuclear localization signal, a cell binding motif, and a catalytic domain. This protein has been shown to be both neurotrophic and neuroprotective and the mature protein has antimicrobial activity against some bacteria and fungi, including S. pneumoniae and C. albicans. Due to its effect on rRNA production and angiogenesis this gene plays important roles in cell growth and tumor progression. Mutations in this gene are associated with progression of amyotrophic lateral sclerosis (ALS). This gene and the neighboring RNase4 gene share promoters and 5' exons though each gene then splices to a distinct 3' exon containing the complete coding region of each gene. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2020]

RNASE4 (HGNC:10047): (ribonuclease A family member 4) The protein encoded by this gene belongs to the pancreatic ribonuclease family. It plays an important role in mRNA cleavage and has marked specificity towards the 3' side of uridine nucleotides. Alternative splicing results in four transcript variants encoding the same protein. This gene and the gene that encodes angiogenin share promoters and 5' exons. Each gene splices to a unique downstream exon that contains its complete coding region. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-20693325-G-C is Benign according to our data. Variant chr14-20693325-G-C is described in ClinVar as [Benign]. Clinvar id is 1288180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0253 (3849/152350) while in subpopulation SAS AF= 0.0474 (229/4832). AF 95% confidence interval is 0.0424. There are 66 homozygotes in gnomad4. There are 2040 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANG	NM_001097577.3	c.-18-222G>C		intron_variant		ENST00000397990.5	NP_001091046.1
RNASE4	NM_002937.5	c.-17-6030G>C		intron_variant		ENST00000555835.3	NP_002928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANG	ENST00000397990.5	c.-18-222G>C		intron_variant		1	NM_001097577.3	ENSP00000381077	P1
RNASE4	ENST00000555835.3	c.-17-6030G>C		intron_variant		1	NM_002937.5	ENSP00000452245	P1

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3850 AN: 152232 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.00569

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00730

Gnomad SAS AF: 0.0476

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0229

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0253 AC: 3849 AN: 152350 Hom.: 66 Cov.: 32 AF XY: 0.0274 AC XY: 2040 AN XY: 74504

Gnomad4 AFR AF: 0.00568

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00732

Gnomad4 SAS AF: 0.0474

Gnomad4 FIN AF: 0.0706

Gnomad4 NFE AF: 0.0331

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0287 Hom.: 14

Bravo AF: 0.0197

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.040
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs117362930; hg19: chr14-21161484;