chr14-20693226-T-G

Position:

• chr14-20693226-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002937.5(RNASE4):​c.-17-6129T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0541 in 152,324 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.054 (319 hom., cov: 32)
• Consequence: RNASE4 NM_002937.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.488

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-20693226-T-G is Benign according to our data. Variant chr14-20693226-T-G is described in ClinVar as [Benign]. Clinvar id is 1286899.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANG	NM_001097577.3	c.-18-321T>G		intron_variant		ENST00000397990.5
RNASE4	NM_002937.5	c.-17-6129T>G		intron_variant		ENST00000555835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANG	ENST00000397990.5	c.-18-321T>G		intron_variant		1	NM_001097577.3	P1
RNASE4	ENST00000555835.3	c.-17-6129T>G		intron_variant		1	NM_002937.5	P1

Frequencies

GnomAD3 genomes AF: 0.0541 AC: 8233 AN: 152206 Hom.: 319 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0385

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.160

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0545

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

GnomAD4 genome AF: 0.0541 AC: 8239 AN: 152324 Hom.: 319 Cov.: 32 AF XY: 0.0568 AC XY: 4230 AN XY: 74480

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.0383

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.0922

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0605

Gnomad4 OTH AF: 0.0573

Alfa AF: 0.0592 Hom.: 37

Bravo AF: 0.0468

Asia WGS AF: 0.130 AC: 451 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.63
DANN	Benign	0.50

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: rs74792371; hg19: chr14-21161385;