chr14-20693226-T-G

Variant names:

• chr14-20693226-T-G
• rs74792371
• NM_001097577.3:c.-18-321T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 publications found

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]

ENSG00000259171 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002937.5. 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
	ANG	NM_001097577.3	MANE Select	c.-18-321T>G		intron	N/A	NP_001091046.1	P03950
	RNASE4	NM_002937.5	MANE Select	c.-17-6129T>G		intron	N/A	NP_002928.1	P34096
	ANG	NM_001145.4		c.-18-321T>G		intron	N/A	NP_001136.1	P03950

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANG	ENST00000397990.5	TSL:1 MANE Select	c.-18-321T>G		intron	N/A	ENSP00000381077.4	P03950
	RNASE4	ENST00000555835.3	TSL:1 MANE Select	c.-17-6129T>G		intron	N/A	ENSP00000452245.1	P34096
	ANG	ENST00000336811.10	TSL:1	c.-18-321T>G		intron	N/A	ENSP00000336762.6	P03950

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

African (AFR) AF: 0.0215 AC: 894 AN: 41574

American (AMR) AF: 0.0383 AC: 587 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3470

East Asian (EAS) AF: 0.160 AC: 828 AN: 5184

South Asian (SAS) AF: 0.0922 AC: 445 AN: 4826

European-Finnish (FIN) AF: 0.102 AC: 1080 AN: 10610

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0605 AC: 4118 AN: 68036

Other (OTH) AF: 0.0573 AC: 121 AN: 2112

Alfa AF: 0.0562 Hom.: 429

Bravo AF: 0.0468

Asia WGS AF: 0.130 AC: 451 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.90
CADD	Benign	0.63
DANN	Benign	0.50
PhyloP100		-0.49
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: rs74792371; hg19: chr14-21161385;