rs8004382

Variant names:

• chr14-20687234-A-G
• rs8004382
• NM_002937.5:c.-18+2476A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-20687234-A-G
• chr14-20687234-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002937.5(RNASE4):​c.-18+2476A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 152,102 control chromosomes in the GnomAD database, including 22,794 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (22794 hom., cov: 33)
• Consequence: RNASE4 NM_002937.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.53
• Publications: 9 publications found

Genes affected

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]

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]

ANG Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259171 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.605 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
	RNASE4	NM_002937.5	MANE Select	c.-18+2476A>G		intron	N/A	NP_002928.1	P34096
	ANG	NM_001145.4		c.-19+2476A>G		intron	N/A	NP_001136.1	P03950
	RNASE4	NM_001282192.2		c.-122+2476A>G		intron	N/A	NP_001269121.1	P34096

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASE4	ENST00000555835.3	TSL:1 MANE Select	c.-18+2476A>G		intron	N/A	ENSP00000452245.1	P34096
	ANG	ENST00000336811.10	TSL:1	c.-19+2476A>G		intron	N/A	ENSP00000336762.6	P03950
	ENSG00000259171	ENST00000553909.1	TSL:2	c.-19+2476A>G		intron	N/A	ENSP00000477037.1	V9GYS4

Frequencies

GnomAD3 genomes AF: 0.546 AC: 83046 AN: 151984 Hom.: 22771 Cov.: 33

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.550

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.600

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.534

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

GnomAD4 genome AF: 0.546 AC: 83116 AN: 152102 Hom.: 22794 Cov.: 33 AF XY: 0.548 AC XY: 40756 AN XY: 74344

African (AFR) AF: 0.611 AC: 25362 AN: 41478

American (AMR) AF: 0.473 AC: 7238 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1849 AN: 3468

East Asian (EAS) AF: 0.600 AC: 3108 AN: 5180

South Asian (SAS) AF: 0.511 AC: 2464 AN: 4826

European-Finnish (FIN) AF: 0.560 AC: 5920 AN: 10564

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35375 AN: 67980

Other (OTH) AF: 0.531 AC: 1120 AN: 2110

Alfa AF: 0.527 Hom.: 64932

Bravo AF: 0.545

Asia WGS AF: 0.545 AC: 1896 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.13
DANN	Benign	0.50
PhyloP100		-2.5
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: rs8004382; hg19: chr14-21155393;